CD/CV and Goldstein
Everyone seems to be talking about this NY Times interview with David B. Goldstein (Gene Sherpas, biomarker-driven mental health, Adaptive Complexity, John Hawks …)
In the proud tradition of blogging, I will add my voice to the noise.
The common disease / common variant hypothesis
The arguments concern association mapping and the so-called Common Disease / Common Variant (CD/CV) hypothesis. The CD/CV goes like this: a lot of common diseases are late-onset, so we do not expect selection to be strong against the genetic factors underlying them. This, combined with the recent expansion in the human population leads us to expect that a lot of common diseases to be caused by relatively common variants.
If the hypothesis is true, then we should be able to locate these common variants since we can tag all common variants in the genome with relatively few markers, and we can type these using SNP chips.
If the hypothesis is false, then we are screwed. We probably need complete re-sequencing and some heavy duty statistics to get anywhere.
Out of convenience more than anything, people chose to believe the CD/CV to be true, and started projects such as HapMap to map the common variation in the genome. Based on this map, companies developed chips to tag all variation genome wide, and disease studies used these chips to do genome wide scans.
Goldstein argues:
It takes large, expensive trials with hundreds of patients in different countries to find even common variants behind a disease. Rare variants lie beyond present reach. “It’s an astounding thing,” Dr. Goldstein said, “that we have cracked open the human genome and can look at the entire complement of common genetic variants, and what do we find? Almost nothing. That is absolutely beyond belief.”
If rare variants account for most of the genetic burden of disease, then the idea of decoding everyone’s genome to see to what diseases they are vulnerable to will not work, at least not in the form envisaged. “I don’t believe we should do more and more genomewide association studies for common diseases,” Dr. Goldstein said. Instead, he suggested, the “missing heritability” might be tracked by thoroughly studying the genome of specific patients.
I would say the jury is still out on this one, but it is clear that the CD/CV isn’t as common as it was hyped to be. We can only explain a small percentage of the heritability of diseases with the variants found so far. Still, we have discovered more variants that we can replicate within the last year or two than in all the time up to genome wide scans, so writing off genome wide association studies completely is a bit extreme, in my view.
No, CD/CV is not the full story, but some common variants exist, cause we have found them!
The real question is, of course, how much heritability is explained by common variants and how much by rare variants. Right now, we simply do not know. The power to detect even common variants is limited, so there might be more out there to find. On the other hand, it is hard to believe that the vast majority of the heritability is caused by common variants since we still can only explain very little of it, so some rare variants must be involved.
In the coming few years we will probably figure this out, and that is exciting indeed.
Common disease and selection
Now as for variants behind common diseases being selectively (near) neutral — part of why they can be common in the first place — that is an interesting question.
I personally think that selection is playing a larger part in the story of common diseases than we think, and I look forward to learning this story.
Are we seeing common variants because bottlenecks have reduced selection strength so rare variants — otherwise selected against – have managed to increase in frequency by drift? Are we seeing common variants because they are selected for by some balancing selection? Are they hitch-hiking on beneficial variants?
We are already hearing about interesting findings in here (Helgason et al. 2007, Blekhman et al. 2008) and we will learn much more in the future.
We live in interesting times indeed, and now is not the time to abandon genome wide association studies.
September 17th, 2008 at 3:18 pm
Great Post – interesting times indeed and glad to see that the medical genetics discussion is increasingly tied together with the human history and natural selection story. From the genome’s point of view, the human evolutionary story is inextricably linked to the health applications story. In the area of mental health, I think this singular tale will help bust a lot of the stigma that comes with mental illness so its great to see the conversation ‘evolving’.
September 17th, 2008 at 5:32 pm
Great page Thomas Jensen.
David is just reciting the basic principles of population and quantitative genetics. There is bound to be a spectrum of allele effects, and those with strong effects on traits associated with fitness will tend to be at low frequency and those with weaker effects can arise in frequency. As you are all to aware of then population history, drift and selection can lead to some variants with substantial effects rising to the “common” category, but the bulk of the variation is going to be shaped by purifying selection. Hence most mutations affecting disease will be at low frequency, and for the most part invisible from our current arsenal of techniques.
So David was just mentioning what should have been obvious from the start, and what stares us in the face when we add up the genetic components…bulk is still unexplained. Science breakthrough of the year 2007, for the icicle at the of top of the iceberg.
September 17th, 2008 at 5:48 pm
Arnar, my name is not Jensen and hasn’t been for several years ;-)
Anyway, good to hear from you again.
Yes, I know the arguments for why we would expect disease to be explained by rare variants. Actually, why we would expect them to be rare if they are selected against (which CD/CV assumes is not the case, or at least that the selection is weak compared to the time since the human population size expansion).
I guess it is a question of whether you can believe that variants behind common diseases are selectively neutral. I’m not completely buying it, but I haven’t actually done the math to figure out how much selection you can get away with and still see common variants, when you include the expansion in the calculations…
September 18th, 2008 at 11:45 am
Dr. Mailund
The less friendly side of me wrote the greeting, pardon me for exposing the past.
Perhaps the disease variants need not be neutral, as the human effective population size is small there is plenty of room for drift, raising the frequency of slightly or even moderatly deletrious mutations. As you discuss the role of variable selection pressures across the globe and cultures can alter the frequency of alleles with environmentally dependent effects (thifty gene, and related theories).
I also wonder if about the degree of tribalism in human history, which must increase the effect of drift.
Good to see you are doing well, keep it up.
September 18th, 2008 at 1:59 pm
Arnar, the point about selection and the effective population size is exactly why the recent expansion of the human population size is used as an argument for CD/CV. Even if a trait is selected against now, it might not have been a few hundred K years ago when the population was smaller, and if the frequency of alleles just after the expansion matches the frequency of alleles before the expansion, then an allele selected against could be in a much higher frequency than expected, Ne and selection taken into account. It then takes some time for it to drop in frequency again, but that time is too long for us to see it yet.
At least that is how I remember the argument…