Height and hypertension genes in Nature Genetics

The advance online edition of Nature Genetics is stuffed with juicy complex human genetics goodness.

Firstly, there are three massive genome-wide scans for genes involved in regulating human height, each of which analysed more than ten thousand individuals. As I've mentioned before, height appears to be one of those traits (like bipolar disease) that thumbs its nose at genome-wide association studies (GWAS). That's evidently clear from these studies, each of which - despite their unprecedented size (one of them scanned more than 25,000 individuals!) - managed to capture variants explaining less than 5% of variation in height.

I note that a few previously identified height genes, like HMGA2 and GDF5, pop up in more than one of the three studies, while a new gene (ZBTB38) appears as the top candidate in all three of the studies. However, there doesn't seem to be a huge amount of overlap in the lower-ranked genes (although I need to read the articles more carefully to be sure).

ScienceDaily puts a positive spin on the story ("Scientists are beginning to develop a clearer picture of what makes some people stand head and shoulders above the rest"), but the real story is this: despite the massive scale of these studies, they're still only capturing less than 5% of the total variance in a trait that is almost entirely (~80%) genetic. This is a powerful demonstration of the inability of current GWAS technology to access the genetic variants responsible for the vast majority of heritable variation in at least some complex traits, for reasons I've discussed recently.

Researchers interested in the genetics of common diseases are no doubt experiencing a sinking feeling as they read these studies, since there's every reason to expect that what holds true for height will also apply in at least some of these conditions. If so, the number of patients required to characterise even a trivial proportion of the total genetic risk using GWAS will be astronomical. However, there is a light at the end of the tunnel: large-scale sequencing, once it drops in price, will provide researchers with access to the rare variants and structural variation currently missed by chip-based GWAS technologies, and should help to capture a substantial proportion of the missing variation.

This leads into another Nature Genetics article, which used an interesting candidate gene resequencing strategy to detect variants linked with variation in blood pressure. Readers persistent enough to slog through yesterday's post on the genetics of bipolar disease might recall that hypertension is another disease in which the GWAS approach has yielded little success; in the comments to that post, G from Popgen ramblings notes that admixture mapping (an approach to gene identification using populations with mixed ancestry) has also failed to produce consistent signals, despite a profound difference in hypertension risk between populations.

The Nature Genetics study took a different approach, sequencing the full coding regions of three genes associated with rare, serious hypertension conditions in previous family studies in more than 3,000 individuals from the Framingham Heart Study cohort. They found a scattering of rare variants - all present in a single copy in any given individual - with either inferred or biochemically verified effects on protein function. When the individuals carrying these rare mutations were analysed as a group they showed significantly lower blood pressure than non-carriers.

This combination of targeted resequencing and functional analysis is a difficult road, but it's one that researchers will have to follow increasingly often as they attempt to characterise the rare variants that likely comprise a significant fraction of common disease risk. I'll have more to say about this in future posts.


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