Self evident but unexplored – how genetic effects vary over time

A new paper in PNAS reports on how the effect of a variant of a gene called FTO varies over time. Previous research has shown that people with two copies of a particular FTO variant are on average three kilograms heavier than those with none. But this was not always the case. I’ll let Carl Zimmer provide the background:

In 1948, researchers enlisted over 5,000 people in Framingham, Mass., and began to follow their health. In 1971, the so-called Framingham Heart Study also recruited many of the children of original subjects, and in 2002, the grandchildren joined in. In addition to such data as body mass index, the researchers have been gathering information on the genes of their subjects.

The scientists compared Framingham subjects with the risky variant of FTO to those with the healthy variant. Over all, the scientists confirmed the longstanding finding that people with the risky FTO variant got heavier.

People born before the early 1940s were not at additional risk of putting on weight if they had the risky variant of FTO. Only subjects born in later years had a greater risk. And the more recently they were born, the scientists found, the greater the gene’s effect.

Some change in the way people lived in the late 20th century may have transformed FTO into a gene with a big impact on the risk of obesity, the researchers theorized.

This result is unsurprising. It is standard knowledge that genetic effects can vary with environment, and when it comes to factors likely to influence obesity such as diet, there have been massive changes to the environment over time. As the authors of the PNAS paper note:

This idea, that genetic effects could vary by geographic or temporal context is somewhat self-evident, yet has been relatively unexplored and raises the question of whether some association results and genetic risk estimates may be less stable than we might hope.

It is great that the authors have provided a particular example of this change. And also useful, the study provides another response to the claim genetics is not relevant to increases in obesity because there has been limited genetic change since levels of obesity took off. The high heritability of obesity has always pointed to the relevance of genetics, but this paper strengthens the case.

In his NY Times piece, Carl Zimmer quotes study co-author Nicholas Christakis on whether the changing role of genes may be a more general phenomenon:

Dr. Nicholas A. Christakis, a sociologist and physician at Yale University and a co-author of the new study, suggested that the influence of many other genes on health had waxed and waned over the past century. Reconstructing this history could drastically influence the way doctors predict disease risk. What might look like a safe version of a gene today could someday become a risk factor.

“The thing we think is fixed may not be fixed at all,” said Dr. Christakis.

I have written before about another example of the changing effect of genes over time – the effect of genes on fertility.

Before the demographic transition when fertility rates plunged in the world’s developed countries, the heritability of fertility was around zero. This is unsurprising as any genetic variation in fitness is quickly eliminated by natural selection.

But when you look at the heritability of fertility after the demographic transition, things have changed. The heritability of fertility as derived from twin studies is around 0.2 to 0.4. That is, 20 to 40 per cent of the variation in fertility is due to genetic variation. People with different genes have responded to changes in environment in different ways.

The non-zero heritability of fertility has some interesting implications for long-term fertility. My working paper outlines the research on the heritability of fertility in discussing these long-term implications. I have posted on the working paper here.

6 comments

  1. Got a question for you that I realize you may not be able to answer.

    I had my genes run by 23andMe and in the raw data they do report on the FTO gene. They list a lot of SNP’s for that gene. How would I know if I have the risky variant? I’m curious because I’ve struggled with weight management my whole life, sometimes having it under control and sometimes not.

    Thanks!

    -George

    1. 23andme report on SNP rs3751812 – which isn’t the relevant FTO SNP but it is likely co-inherited so 23andme consider it close enough. 23andme reports whether you have GG, GT or TT – T is associated with higher body weight.

  2. the study provides another response to the claim genetics is not relevant to increases in obesity because there has been limited genetic change since levels of obesity took off.

    Well, those people are idiots:

    Obesity Facts | JayMan’s Blog

    This idea, that genetic effects could vary by geographic or temporal context is somewhat self-evident

    Temporal, yes. Spatial is not holding up so well, oddly enough.

    Before the demographic transition when fertility rates plunged in the world’s developed countries, the heritability of fertility was around zero. This is unsurprising as any genetic variation in fitness is quickly eliminated by natural selection.

    Precisely. Any extant genetic variation must, out of necessity, be:

    1. Fitness neutral or nearly so.
    2. Result of mutation-selection balance (genetic load).
    3. Due to a recent change in environment.

    (On #3, as Greg Cochran said, “every society selects for something”).

    Previously neutral genes may start to have fitness consequences in a new environment. This is you how you get the change in heritability you describe.

  3. The obverse of which is the common medical saying “if everyone smoked then lung cancer would be a genetic disease”

  4. I found it curious that few of the news articles covering this study highlighted the most influential environments on epigenetic DNA changes: the mother’s environment provided for the fetus, and the family environment during infancy and early childhood.

    Digging deeper, this omission may have been because the study intentionally didn’t support such an interpretation. Here’s a partial explanation of the family-fixed model the researchers used, from the supplementary material: “the family fixed-effects model blocks both genetic factors and parental characteristics/behaviors that are common to family members (e.g., siblings), including unmeasured factors; therefore, from the perspective of confounding, the fixed-effect specification is preferred.”

    When the preferred model blocks the most important environments in which epigenetic DNA changes occur, what environments remain? “These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.”

    Although a finding attributing “global environmental changes” makes more funding available to the researchers, it is rightly an outlier from the majority of epigenetic studies.

    In my view, it’s a directed finding where the model defines away both the out-of-favor genetic factors and the predominant but unpolitically-correct epigenetic factors in favor of a politically correct epigenetics meme.

    How else to interpret this sentence? “Our results underscore the importance of interpreting any genetic studies with a grain of salt and leave open the possibility that new genetic risk factors may be seen in the future due to different genetically driven responses to our ever-changing environment.”

    http://surfaceyourrealself.com/2015/02/17/problematic-research-that-excludes-the-most-influential-human-epigenetic-environments-surfaceyourrealself/

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