29 January 2011

Genome-wide association studies and the "missing heritability".

From The Golden Helix blog:
" If complex diseases are driven by susceptibility alleles that are ancient common polymorphisms, as the common diseases-common variant hypothesis proposes, we should be seeing a larger portion of the heritability of these traits being accounted for by these associated polymorphisms. The alternative hypothesis that must now be considered is that complex diseases are actually driven by heterogeneous collections of rare and more recent mutations, as with most Mendelian diseases!"

Quite a lot of us have been considering that hypothesis for a rather long time. GWASs have been able to detect quite a number of genes involved in complex and common disease, but common variations in the population can only explain a relatively small amount of the "heritability". A rough way of thinking about this is to consider all the genetic variation that we know about in a population - every new generation injects a vast amount of completely new variation - you contain about 100 mutations that your parents did not have. Your kids will each have another 100, and this is happening for everyone within the population. Many of these mutations are going to occur in genes that participate in pathways that will affect disease susceptibility - it is unavoidable.
For the purposes of this discussion (the reality, as ever, is a bit more complex), "Mendelian diseases" are those rare (but actually not that rare!) disorders that are caused by mutations of large effect on one critical gene; different disorders are caused by mutations in different genes, and exert their effect by disruption of different biological pathways. Having a rare disorder is a common problem - something like 10% of families are impacted by a serious genetic disease. They crop up all the time; that being the case, why should it come as a surprise that genes influencing heart disease or autism crop up all the time at a low enough frequency to be missed by GWAS, but frequent enough to make the diseases themselves very common?
Clinical geneticists have been saying this for a while now - but are they correct? The exciting thing is that the possibility to test these ideas is arising from the technology that allows us to sequence large numbers of human genomes relatively cheaply, and to analyse biological pathways in unprecedented depth. With large datasets like these, we will be able to avoid the inherent bias of GWAS for common genetic variants, and get a better picture of the fine scale genetic structure - many many rare variants in gene pathways that can cause disease susceptibility. That is when the fun will really start.
But it'll be nice to be able to say "We told you so!"...

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