Can we or can't we explain common disease?

Rare variants don't explain disease risk
We're still catching up on readings after a long Thanksgiving weekend, so are just getting to last week's Science.  Here's a piece that's of interest -- 'Genetic Influences on Disease Remain Hidden,' Jocelyn Kaiser -- in part because it touches on a subject we often write about here, and in part because it seems to contradict a story getting big press this week, published in this week's Nature.

Kaiser reports from the Human Genetics meetings in San Francisco that finding genes for common disease is proving to be difficult.  GWAS, it turns out, are finding lots of genes with little effect on disease.  This is of course not news, though the Common Variant/Common Disease hypothesis -- the idea that there would be many common alleles that explain common diseases like heart disease and type 2 diabetes -- died far too slowly given what was obvious from the beginning (never with any serious rationale, as some of us had said clearly at the time, we may not-so-humbly add), and the rare variants hypothesis that replaced it is rather inexplicably still gasping.  Or, as Kaiser writes, "...a popular hypothesis in the field—that the general population carries somewhat rare variants that greatly increase or decrease a person's disease risk—is not yet panning out."

Apparently the idea, then, is that there's still hope. Indeed, many geneticists believe that larger samples are the answer.  That is, studies that include tens or hundreds of thousands of individuals, because these will be powerful enough to detect any strong effect rare variants may have on disease, in theory explaining the risk in the center of the graph from the paper, which we reproduce here.  Kaiser cites geneticist Mark McCarthy of the University of Oxford in the United Kingdom: “We're still in the foothills, really. We need larger sample sizes."  Further, he says, "The view that there would be lots of low frequency variants with really big effects does not look to be well supported at the moment." 

Fig from Kaiser. New studies failing to explain the genetics of common disease.  

Even with larger sample sizes, it turns out that some variants are so rare that they're only seen once.  And probably explain only a small proportion of risk anyway, even in that single individual. And certainly can't be used to predict disease. But this doesn't stop geneticists from wanting to increase sample sizes, at this point usually by doing exome sequencing (sequencing all the exons, or protein coding regions) of tens of thousands of people and looking for rare variants with large effects.  Ever hopeful.  McCarthy, a seriously non-disinterested party to any such discussion, is not likely to give up on ever-larger scale operations; that would be research-budget suicide, regardless of the plausibility of the rationales.

Rare variants do explain disease risk
Which brings us to the big news story of the week, a paper in Nature by geneticist Josh Akey et al., described in a News piece by Nidhi Subbaraman in the same journal, 'Past 5,000 years prolific for changes to human genome.'  The idea is that the rapid population growth of the last 5,000 years has resulted in many rare genetic variants, because every generation brings new mutations, and that these are the variants that are most likely to be responsible for disease because they haven't yet been weeded out of the population for being deleterious.

The research group sequenced 15,336 genes from 6,515 European Americans and African Americans and determined the age of the 1,146,401 variants they found.  "The average age across all SNVs was 34,200 ± 900 years (± s.d.) in European Americans and 47,600 ± 1,500 years in African Americans..."  They estimated that the large majority of the protein-coding, or exonic single nucleotide variants (SNVs) "predicted to be deleterious arose in the past 5,000-10,000 years."  Genes known to be associated with disease had more recent variants than did non-disease genes, and European Americans "had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans..."

They conclude that their "results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery."  Indeed, the proportion of SNVs in genes associated with Mendelian disorders, complex diseases and "essential genes" (those for which mouse knockouts are associated with sterility or death) that were 50,000 to 100,000 years old was higher in European Americans than in African Americans.  The authors propose that this is because these variants are associated with the Out-of-Africa bottleneck as humans migrated into the Middle East and Europe, which "led to less efficient purging of weakly deleterious alleles."

The researchers conclude:

In summary, the spectrum of protein-coding variation is considerably different today compared to what existed as recently as 200 to 400 generations ago. Of the putatively deleterious protein-coding SNVs, 86.4% arose in the last 5,000 to 10,000 years, and they are enriched for mutations of large effect as selection has not had sufficient time to purge them from the population. Thus, it seems likely that rare variants have an important role in heritable phenotypic variation, disease susceptibility and adverse drug responses. In principle, our results provide a framework for developing new methods to prioritize potential disease-causing variants in gene-mapping studies.  More generally, the recent dramatic increase in human population size, resulting in a deluge of rare functionally important variation, has important implications for understanding and predicting current and future patterns of human disease and evolution. For example, the increased mutational capacity of recent human populations has led to a larger burden of Mendelian disorders, increased the allelic and genetic heterogeneity of traits, and may have created a new repository of recently arisen advantageous alleles that adaptive evolution will act upon in subsequent generations.

This does seem to contradict the Kaiser piece we mention above, which concludes that rare variants with large effect will not turn out to explain much common disease.  This paper suggests they will -- which we don't think is right, for reasons we write about all the time.  But it does lend support to the idea that the Common Variant/Common Disease hypothesis is dead and buried. 

Serious questions
It is curious, and serious if true, that Africans harbor fewer rare variants than Eurasians.  African populations expanded rapidly since agriculture, just as Eurasians did.  It could be, but seems like rather post-hoc rationalizing, that Africa is more dangerous to live in, even for only mildly harmful variants.  Rapid expansion--the human gene lineages have expanded a million-fold in the last 10,000 years, will lead to many slightly harmful variants being around at low frequency, because slight effects aren't purged by selection as fast as they are generated in an expanding population.

In a sense the deluge has not been of functionally important but rather functionally minimal variants.  Maybe there is something about the raised probability that a person will have a combination of such variants, and the variants could be found by massive samples.  But then their individual effect probably isn't worth the cost of finding them, as a rule.

But where's the nod to complexity?
But, environments change, and genes now considered to be deleterious may not have been so in previous environments, or may even have been beneficial.  And African Americans don't represent a random sample from the entire African continent, as their ancestry is predominantly West African, and SNV patterns are likely to be different in different parts of Africa.  And, numerous studies have found that healthy people carry multiple 'deleterious' alleles, so the idea that 84% of SNVs will lead to disease is probably greatly exaggerated. Geneticists just can't bring themselves to acknowledge that complexity trivializes most individual genetic effects.

The more likely explanation for complex disease continues to be, "It's complex."