Disease: global & historical context

By Razib Khan | May 29, 2013 1:41 am

Citation: Corona, Erik, et al. “Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration.” PLoS Genetics 9.5 (2013): e1003447.

The above figure is from a paper in PLoS GENETICS, Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration. The authors synthesize two diverse domains of human genomics. First, there are biomedically focused genome-wide association studies and their like which attempt to identify risk alleles for particular diseases. In some cases these risk alleles are very penetrant, in that a particular state predicts with high likelihood a disease phenotype. But in most cases the yield is elevated or decreased risks for highly complex traits such as type 2 diabetes. Second, there is the domain of evolutionary genomics which attempts to reconstruct a phylogenetic and population genetic history so as to frame contemporary patterns of variation in their proper context. How this might be important or of interest is obvious in the case of malaria resistance genes. Alleles conferring resistance have arisen in multiple populations due to parallel environmental pressures. Phylogenetic relationships between these populations should inform your predictions as to the likely similarities of the mutations between the populations. Meanwhile, population genetic theory can give you clues as to the likelihood of multiple adaptations.

The goal here is to increase understanding of the nature of the emergence of disease, and perhaps target individual risk more effectively. Above in the figure you see two interesting patterns: risk for type 2 diabetes alleles as a function of descent, and risk as a function of de novo mutation or independent selective event. The phylogenetic tree represents real relationships as inferred from the >600,0000 SNPs in the HGDP data set. The risk alleles were culled from the literature, and were computed for individuals and populations. The real population risks were then compared to a model of risks which might occur in a scenario with this particular phylogenetic tree and the normal process of random genetic drift (see methods for the gory details!). What you see are phylogenetic relationships (African populations shifted toward higher risk) and independent events (Pima Indians shifted toward higher risk) where there is a higher risk toward diabetes (red shifted).

There are all sorts of shortcomings to this analysis. The authors are limited by the risk alleles in their study, which is certainly far less than thorough or exhaustive. Additionally, their population coverage was thin in some regions, resulting in reduced ability to even squeeze power from their model in particular cases. But one thing that jumps out at you is that the patterns here inferred from risk alleles in a highly polygenic disease like type 2 diabetes don’t even track what you see in the real world. Many South Asian groups have very high risks of type 2 diabetes. It just so happens that these groups are not in the HGDP sample. There is actually a rather informative critique from two epidemiologists in the comments of this paper. They make many points that came to mind in the specifics. But they ended in a fashion which raised my eyebrows:

Finally, the need to avoid stigmatizing populations based on genetic risk has been much discussed.It is not difficult to imagine a media announcement based on this publication – “Genetic risk of diabetes found in African populations”. Similar claims were made for intelligence not very long ago. Not all speculation is neutral.

As it happens I come from a population with very high risk for metabolic disease. I have no idea if I’m stigmatized by this fact, but I am very glad that medical professionals are becoming aware of differential risks, and moving beyond coarse one-size-fits-all understandings of human health. The BMI values developed for European Americans are probably rather inappropriate to South Asians because of the way we distribute fat (in short, we need to be thinner to exhibit the same risk profile all things equal). Again , I have no idea if this is stigmatizing, but it is real.

So despite all the real concerns I have with the methodology in the paper above, I believe that these sorts of analyses are essential parts of the broader answer. We now live in the age of the antiobiotic revolution and an understanding of germ theory. Those were the big returns on investment for public health. For the short term gains in human well being and life expectancy are going to be on the margin, through increments. Despite all the skepticism I have with initial attempts to work out the relationship between population history and disease, one must begin somewhere.

Citation: Corona, Erik, et al. “Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration.” PLoS Genetics 9.5 (2013): e1003447

  • https://delicious.com/robertford Robert Ford

    That’s the weirdest ending to a paper. Is that common? “Oh, and by the way, we’re definitely not racist!”

    • razibkhan

      just to be clear, the comment was attached by other people as a comment to the paper on PLoS. I thought the comment was pretty good as far as it goes (informative, on point). but since epidemiology seems to acknowledge differential risk i have no idea why they would point that out as an issue.

      • https://delicious.com/robertford Robert Ford

        my bad, I didn’t read that clearly. PC police on patrol at PLOS Genetics!

        • razibkhan

          seems like a throwaway line. but also frankly rude in light of the aims/intent of the authors. a very, very, long way from the proper population genetic framing of disease risk to the genetics of intelligence.

          • https://delicious.com/robertford Robert Ford

            The cynic in me thinks it almost feels like a threat. If I were one of the authors I would ask him to remove it.

    • http://entitledtoanopinion.wordpress.com TGGP

      Are you referring to the comment Razib quoted? That’s not from the authors.

  • marcel proust

    I thought I posted the following question earlier, but don’t see it so I’ll try again:

    The BMI values developed for European Americans are probably rather inappropriate to South Asians because of the way we distribute fat (in short, we need to be thinner to exhibit the same risk profile all things equal).

    Any speculations as to the source of this difference? What occur to me are: (1) more variable climate in Europe leading to more frequent famines, (2) much colder winters in much of Europe, requiring more insulating fat, and (3) one harvest per year vs. several per year, leading to annual food shortages in the late spring, early fall (I cannot recall the term for this: “hunger times”?) when the remains of the previous years harvest were gone and nothing from the current year’s harvest was yet ready. But these are the equivalent of, as they say, on-the-veldt explanations.

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Gene Expression

This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!

About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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