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'An Artificial Argument'

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Recently, researchers have been discussing how genetic variants may affect a person's disease risk. Andrew Singleton, a researcher in the National Institute on Aging's neurogenetics lab, tells GT's Ciara Curtin that both common and rare variants — as well as those that fall in between — may play a role in disease.

Genome Technology: What do you think of the common disease/common variant hypothesis? Has it been helpful in understanding disease risk?

Andrew Singleton: You have groups taking total opposite views and almost creating an artificial argument. The artificial argument at the moment is common disease/common variant hypothesis or is disease modulated by rare risk variants. They are not mutually exclusive hypotheses. Clearly, the results of genome-wide associations have identified lots of risk variants for common diseases and these are, by definition, common risk variants. There's without doubt merit to the common disease/common variant hypothesis. I think that what we're starting to get a handle on is that there aren't many things like ApoE, for Alzheimer's disease, where it is a common variant and it exerts a really strong effect. For really common diseases, what we're seeing is common risk alleles that exert really small effects [on] lifetime risk for disease and there might be many of these for common disease. Now, that doesn't preclude there being rare variants that affect disease also.

GT: What do you think the role of rare variants will be?

AS: I think they will be important in disease. The issue with rare variants is that they are going to be extremely hard to show that they are associated with disease. What we're seeing now is almost a gradient of effect. You have these rare disease-causing mutations which are often coding [and] almost invariably cause disease or really, really increase your risk for disease. Then we have coding variants that are common, but don't cause disease, but increase risk for disease. And then we have noncoding common variants which sneak up your risk for disease a little bit. I suspect continuing along there will be rare variants that are noncoding [but] that change lifetime risk for disease. I don't doubt that rare risk variants will exist for disease, but it will be really hard to prove what's the risk variant and what's just benign.

GT: What do you think is the best approach to go from the loci identified by GWAS to actual genes?

AS: I think the most accessible way is to look at the effects of risk variants on, for instance, expression or DNA methylation. One would presume, in the absence of a really striking coding variant on your risk haplotype, that the risk haplotype or the risk variant is affecting gene expression or gene splicing or DNA methylation or all of those things. I actually think that the way to do this is to create fairly large central resources where we measure common genetic variability across the genome and look at the expression in a genome-wide manner, DNA methylation in a genome-wide manner. This is the idea of the GTex project: This is a project that aims to assay common genetic variability in roughly 1,000 individuals and look at expression in 50 tissues from those individuals and create an atlas of effects of common genetic variability on expression.

GT: Anything you'd like to add?

AS
: One thing that's often raised is what is the use of finding rare risk variants? What does it tell us about disease? For every locus that we find, and for every gene that we find associated with that locus, [it] gives us a bit more information about the underlying biology of the disease.

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