Obesity and Genes

I have been meaning to talk about this story, but I have been busy.

A study in Nature looked for genes linked with "common" obesity (more on that in a moment), and it was one of the first to link genes to the disease. Turns out several are genes expressed in the brain:

A genetic study of more than 90,000 people has identified six new genetic variants that are associated with increased Body Mass Index (BMI), the most commonly used measure of obesity. Five of the genes are known to be active in the brain, suggesting that many genetic variants implicated in obesity might affect behaviour, rather than the chemical processes of energy or fat metabolism.

Obesity is an increasing problem that results in individual risk to health as well as increasing burdens on health care systems. By identifying genetic variants that affect obesity, researchers hope to understand better the mechanisms regulating energy balance, which will guide the development of new therapies and help to develop improved diagnosis.

The study is published in Nature Genetics by the GIANT Consortium and includes authors from more than 60 institutions.

"It might seem remarkable that it is the brain that is most commonly influenced by genetic variation in obesity, rather than fat tissue or digestive processes," says Dr Ines Barroso, a senior author on the study, from the Wellcome Trust Sanger Institute. "Until 2007, no genetic associations had been found for 'common obesity', but today almost all those we have uncovered are likely to influence brain function."

(The actual paper is here.)

Just to clarify, "common" obesity is as distinct from monogenic obesity. Monogenic obesity is the result of mutations to single genes. Examples include leptin insufficiency -- a disease where a hormone released from fat cells, leptin, fails to signal to the central nervous system that you have enough fat. In the case of monogenic obesity, the explanation and the solution are pretty simple: replace what's missing. "Common" obesity or polygenic obesity is another matter. It results from the combination of many genes and substantial environmental influence. For more information on this distinction, read this post.

Anyway, Razib and Daniel MacArthur have this story very capably covered, but I would like to make a couple additional comments.

A point that both Razib and Daniel emphasize is that people get the wrong impression when they hear that the heritability of obesity is 40-70%. Heritability does not mean the degree to which a disease is genetic. It means the amount of variance in a population that can be attributed to changes in genes. The heritability may say something about the variance, but it says nothing about the population mean for a trait. Thus, you could have something that is both highly heritable and also highly dependent on environment. For example, think of height. Height is determined by genetics; the children of tall parents are likely to be tall. But it is also determined by the environment; people from societies with good nutrition are also much likely to be taller. Height is both heritable and subject to environmental influence.

We know that obesity has genetic causes. We also know that obesity rates have sky-rocketed since the 60s. Obesity has both genetic and environmental causes.

The other point that I am happy Daniel makes is that the variance associated with these particular genes is relatively minor:

The same paper also reports using their genetic data to come up with a "genotype score", which can be seen as a kind of genetic risk profile for individuals. Even combining all of the available genetic variants the predictive power of this score is pretty meagre:

...the 1.2% (n = 178) of the sample with 13 or more 'standardized' BMI-increasing alleles across these eight loci is on average 1.46 kg/m2 (equivalent to 3.7-4.7 kg for an adult 160-180 cm in height) heavier than the 1.4% (n = 205) of the sample with less than or equal to3 standardized BMI-increasing alleles, and 0.59 kg/m2 (1.5-1.9 kg for an adult 160-180 cm in height) heavier than the average individual in our study.

In other words, the 1.2% of individuals with the "fattest" genes were only 2 kg heavier on average than individuals with "average" genes. That really is pretty minimal predictive information. (Emphasis in original.)

I don't dispute the findings of this study, but saying that someone with all of these genes is only 2 kilos heavier on average is a really small effect size. Polygenic diseases are like that. There are genetic risk factors, but each particular variant has a small effect size.

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Just found your site today - really enjoying it. I skimmed this article and found the following excerpt troubling:

"Increase in weight occurs when calories taken in exceed calories burned..."

Of course, this is built from the First Law of Thermodynamics (Law of Energy Conservation), but it is (more or less) wrong. Or more correctly, applying the First Law of Thermodynamics to obesity in this manner is wrong (of course the law of conservation of energy is correct!). The application makes the following implicit assumption: Energy Intake - Energy Expenditure --> Change in Energy Stores

Notice the change from = to -->, or from correlation to causation.

So a positive caloric association is certainly associated with weight gain, but to say it causes weight gain, adds a "-->" to the First Law of Thermodynamics, when an "=" is what the Law actually says.

See Gary Taubes's fantastic book, The Diet Delusion (in the UK) for some really enlightening insights into Obesity and Obesity research over the last 150 years. A lot of the CW out there (currently) is flat wrong. The sentence I quoted above is an example - and it was an assumption of some heavyweight geneticists.

"I don't dispute the findings of this study, but saying that someone with all of these genes is only 2 kilos heavier on average is a really small effect size."

Bingo, so why is it that so many people are obese today? Is it possible that what people eat (i.e., their environment), what our genetic ancestors certainly did not eat, has a massive impact on how modern man's metabolic and hormonal systems function (or rather how they react to substances that hundreds of thousands of years of evolution have not prepared them for), and even which genes are expressed? I think maybe so.

I'm a bit suspicious of the argument that "gene x is expressed in the brain therefore gene x affects behavior".

There's a lot of energy consumption in the brain, massive blood supply - something like 20% of the human body's energy goes to the brain which is just a couple of percent of the body mass - a gene just affecting metabolism whose effect is to increase the rate of consumption of energy in the brain by 10% would have a much greater effect on the overall metabolic rate than a gene which increases the consumption of energy in the foot (say) by 10%.