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.