The Genetics of Obesity, Part III

Genetics Loads the Gun, Environment Pulls the Trigger

Thanks to a WHS reader* for reminding me of the above quote by Dr. Francis Collins, director of the US National Institutes of Health**.  This is a concept that helps reconcile the following two seemingly contradictory observations:

1. Roughly 70 percent of obesity risk is genetically inherited, leaving only 30 percent of risk to environmental factors such as diet and lifestyle.
2. Diet and lifestyle have a large impact on obesity risk.  The prevalence of obesity has tripled in the last 30 years, and the prevalence of extreme obesity has increased by almost 10-fold.  This is presumably not enough time for genetic changes to account for it.

To explore this concept further, consider two hypothetical examples.  If everyone in Sameville lives in the exact same way and eats the exact same food, environmental variability will not contribute to body fat variability at all.  Genes will be the only major source of variability, and therefore the heritability of body fatness will approach 100%.  Obese people in Sameville almost always have obese children, and lean people almost always have lean children.

If each person in Differentville lives in a radically unique way and eats radically unique food, environmental variability will be huge, and the heritability of body fatness will be lower, perhaps 25%.  High environmental variability means genetics gets a smaller share of the total variability.  In Differentville, obese parents often have lean children and lean parents often have obese children.

As this example illustrates, estimates of heritability only apply within a specific environmental context.  Within the US and within many other affluent countries, most people live in a relatively similar manner (as opposed to comparing the environment of the US vs. Uganda).  If you don't live like the typical 21st century American, and don't eat like the typical 21st century American, then there's no reason to believe that obesity heritability estimates derived from 21st century American studies will apply to you.  By living and eating significantly better than average, many people can escape their genetic tendency toward obesity.

Genes Determine Susceptibility

If genes are so important, how do we explain the fact that numerous traditionally-living cultures around the world remain lean throughout life, with very few overweight individuals, even if they have sufficient food availability, yet these same groups readily become obese once they modernize?  How do we explain the fact that obesity prevalence has increased three-fold in the US since 1978?  My view is that genes don't determine a person's absolute level of body fatness, but they do determine a person's degree of susceptibility to a fattening environment.  The best example I've seen of this phenomenon comes from a blood pressure study conducted in traditional and urban women in New Guinea (Maddocks et al. Med J Australia. 1:1123. 1967).

The following graphs show systolic blood pressure on the horizontal axis, and the percentage of the population at a given blood pressure on the vertical axis (this type of graph is called a histogram).  The top graph represents young and older women from a traditionally-living horticulturalist group in the New Guinea highlands***.  What you can see is that nearly all young women cluster in the healthy range between 100 and 120 mm Hg.  Although the curve representing older women is flatter, it's similar in shape and shares nearly the same peak and mean value.  This is a traditionally-living population that maintains a healthy blood pressure as it ages.  

The bottom graph is from a genetically similar population living in the port city of Hanuabada, where trade has brought in Western processed foods and lifestyles.  What you can see is that the curve for young women looks quite good: it's sharply centered around a healthy blood pressure just as it is in the highlands group.  However, in older women, the curve flattens out considerably and develops a pronounced rightward "tail" representing serious hypertension.  Cardiovascular mortality is probably extremely high at the right end of that tail.  Yet despite the industrial diet and lifestyle, many older women on the left side of the graph maintain a healthy blood pressure!

In a natural environment, genetic differences did not result in very much blood pressure variability (i.e., nearly everyone clustered around a healthy value), and hypertension was uncommon.  In an unhealthy environment, genetic susceptibility presumably started to matter more, population blood pressure variability increased with age, and a large fraction of women developed life-threatening hypertension.

The example above focuses on blood pressure, but essentially the same phenomenon has been demonstrated for obesity (1).  Below is a similar graph of the US population, with body mass index (BMI; a rough measure of body fatness) instead of blood pressure on the horizontal axis.  Each line represents a different time point, beginning with NHANES II (1976-80) and ending in 1999-2004.

You can see that although the difference is less pronounced than the the blood pressure example above, the curve "flattens out" somewhat over time, producing a longer rightward "tail" of obese and extremely obese individuals, and a higher mean value.  Note that the US in 1978 was not quite a "natural environment" by historical standards.  The NHANES II curve has likely already flattened considerably compared to the ancestral population, which would probably exhibit a sharp peak centered around a BMI of ~22, with very little rightward stretch into the obese category.  Also, the curve has shifted even further to the right since 2004, as the prevalence of obesity has increased.

Below is a crude estimate of what the curve probably looked like in the ancestral population (green) prior to industrialization, based on my knowledge of currently existing populations living a subsistence lifestyle.  Leanness is most common, overweight has a modest prevalence, and real obesity is rare but not totally absent.  I've also estimated what the curve looks like in the US today (purple).  I want to be perfectly clear that the colored lines are not real data; I drew them in by hand to illustrate a concept.

You can see that the separation between curves is more pronounced when we consider the entire transition period between the ancestral subsistence lifestyle (green) and the contemporary industrial lifestyle (purple).  Leanness went from typical to atypical, yet there are plenty of lean people even today.  This suggests that when the environment is not fattening, obesity susceptibility genes rarely cause obesity.  When the environment is fattening, susceptibility genes start to matter more, and those who carry them become overweight and obese.  Population BMI variability increases, and the BMI curve flattens out and shifts rightward.

This also suggests that people with a genetic tendency toward obesity would most likely remain lean(ish) in the ancestral environment, and I believe that replicating key aspects of that environment can help us sustain leanness today.

Conclusion

Here are the main points to walk away with:

1. In a healthy environment, genes alone do not usually cause obesity and lifestyle-related diseases, and population variability in these characteristics is low (i.e., most people are lean and free of these diseases).
2. In an unhealthy environment, genetically susceptible people become obese and/or develop disease, while others remain lean and healthy because they are not genetically susceptible.  
3. This results in an increase in population variability (e.g., more variability in body fatness between individuals).
4. Diet and lifestyle environment have a major impact on obesity risk.  For a genetically susceptible person, maintaining a leaner state is usually possible but it requires stepping out of the typical fattening environment.  Genes are not destiny.

* I lost your e-mail.  Send me a message if you'd like attribution.

** Reader Unknown remarked that this quote was used as early as 1920 by Dr. Elliott Joslin.

*** The diet was primarily sweet potatoes.