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Obesity Is Highly Heritable – But Exactly How This Works Remains Mysterious



sharma-obesity-dna_molecule9One of the most fascinating aspects of obesity is that it is virtually as heritable as body height.

Yet, the hunt for the genes that determine body weight has been slow and we are probably not all that much closer to fully understanding exactly how genes influence body weight, than we were 20 years ago, when I myself was dabbling in genetic studies of complex diseases.

An article by the science writer Cassandra Willyard from Madison, Wisconsin, published in the Nature Outlook Supplement on Obesity does a valiant job of explaining where we currently stand in our understanding of the genetics of obesity.

The article discusses the contribution of genome-wide association studies (GWAS), which have linked about 75 genetic variants have to obesity.

“But GWAS studies aren’t perfect. They can lead researchers to important parts of the genome, but it can be difficult to sort out which gene within that region might be the culprit.”

Indeed, it appears that the conventional notion that much of the heritability of obesity would be explained by common genetic variants may be wrong.

Another possibility could well be that current GWAS studies don’t gene-environment interactions into account. Genes that influence body weight only under certain conditions, cannot be identified in the current studies as environmental exposure of individuals has not been well characterized in these studies.

“To resolve the issue, more than a hundred researchers launched a meta-analysis that included 45 studies involving more than 218,000 adults and 19,000 children. Not surprisingly, they found that people who carry the susceptibility gene had a higher risk of obesity. However, the researchers also observed that the risk appears to be reduced in people who are physically active.”

Another possibility may well be that obesity is not determined by common variants but rather by a large number of rare variants in the population (present in less than 5% of individuals, i.e. below the threshold of GWAS analyses).

The article also describes the additional complexity added by the recent work on epigenetics which, of e.g.

…”suggest that what happens in the womb can cause lasting changes in gene expression and influence disease risk even in adulthood, a concept known as fetal programming. This raises the possibility that a mother’s experiences during pregnancy — such as malnutrition — can influence the next generation.”

“The epigenetics of obesity isn’t only about the mother — the father’s experiences can have an impact too. When researchers in Australia fed male rats a fatty diet, the rats — as expected — put on weight and developed signs of diabetes. But, surprisingly, the weight gain also seemed to affect the rats’ daughters: the female offspring had trouble controlling their insulin levels despite being on a normal diet. And a study published in 2013 showed that children with obese fathers had less methylation on a particular region of the IGF2 gene than children who were born to lean fathers.”

As Wollyard explains,

“To show that an epigenetic change is due to inheritance, however, researchers have to look at multiple generations. When a pregnant woman experiences malnutrition or some other environmental stress, three are directly exposed…So, if a woman’s great grandchildren show a particular epigenetic change that is linked to environmental stress during their great grandmother’s pregnancy, that change can be said to be inherited rather than being a programming effect.”

But exactly what role transgenerational transmission of “acquired” genetic changes play in obesity remains unclear. Nevertheless, there is the distinct possibility that this type of inheritance may explain some of the missing heritability.

All we can say, is that there is a considerable likelihood that our genes may well have changed.

@DrSharma
Toronto, ON

2 Comments

  1. I would add to your list of possibilities one other, that we do not have the mathematical framework to account for the non-additive interactions between genetic loci. Most models use an additive presumption, and that SNPs are not synergistic or antagonistic. Given the huge number of them and the difficulty in isolating them, its possible that a large amount of this missing heritability is contained in these unknown interactions (in addition to interactions with environment/epigentics)

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