On the Road to Genetic Architecture

We have been talking about an enzyme encoded by the FTO gene, which sometimes has variants, or alleles, that are alternative forms of the gene. Some of them appear to have connections with obesity and eating disorders, and also with psychopathology. More recent developments have downgraded the presumed importance of the role played by any particular gene in influencing anything.

If it takes a village to raise a child, it takes a whole metropolis of SNPs (single nucleotide polymorphisms) to trigger or perpetuate a somatic disorder, and even more so in the case of a mental illness or to affect cognitive function. The word of the century is “multi-factorial,” and genetic architecture is as multi-factorial as it gets.

The answers are figured out by GWAS, or genome-wide association studies, which involve a ton of fancy mathematics. Human health is ruled by immense numbers of gigantically complicated relationships, in what genomics pioneer Dr. Nilanjan Chatterjee calls “an extremely polygenic model for complex diseases.”

How did we get here?

These ideas are pretty big right now, but what came before? The public, and to a lesser extent the medical profession, hoped to find “the obesity gene.” Although a genetic variant called FTO was a strong candidate, others have been proposed, and then it started to look like maybe everything is weirder than anyone supposed.

Experts have posed a lot of different theories about how genetics and obesity are related, and some of those theories sprang up thanks to the profit motive. At one point Dr. Pretlow wrote,

There are huge vested interests in other obesity medicine research areas, such as genetics, metabolism, and the “built environment.” The premise that obesity is due to food addiction threatens these vested interests.

There might be an indirect connection, with wayward SNPs ganging up to cause a susceptibility to addiction. That weakness could manifest in any number of ways, including addiction to certain foods, or to the mechanistic rituals of eating.

In 2010, a book titled Preventing Childhood Obesity Evidence Policy and Practice stated,

The risk of childhood obesity begins prior to the birth of the child, with genetics as well as the antenatal environment influencing risk of later obesity. It is now recognized that there are many societal and environmental drivers of unhealthy weight gain, and yet most of the research efforts are directed at the individual level, particularly the genetic level…

There seems to be an implication that maybe too many resources were being spent on the genetic angle, to the detriment of more promising fields of inquiry. It is true that such conditions as Cushing’s syndrome, which affects the pituitary gland and causes obesity, can be heritable. Prader-Willi syndrome, which causes obesity, was thought to result from a single determining gene, then came to be regarded as a complex genetic condition. Hypothyroidism, which might originate in a genetic flaw, causes obesity.

These things were known, but also accounted for a very small number of childhood obesity cases. At any rate, gene studies tended to focus on diseases that were, or seemed to be, monogenic.

Dr. Pretlow has asked whether the suspicions of metabolic, genetic, and environmental bases for the obesity epidemic might simply be red herrings. On the other hand, while the simple energy balance equation sounds logical, evidence keeps coming in for “a complex web of interacting biological, societal and behavioral determinants.”

In 2013, the PHG Foundation asserted that…

We — scientists, health professionals and increasingly, the public — have a fairly good understanding of the environmental and even the behavioral factors that lead to weight gain, yet the genetic determinants, in the main, remain elusive.

Your responses and feedback are welcome!

Source: “Preventing Childhood Obesity Evidence Policy and Practice, 2010,” Wiley.com, 2010
Source: “Obesity — a Growing Concern,” PHGFoundation.org, 2013
Image: Photo on Visualhunt

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OVERWEIGHT: What Kids Say explores the obesity problem from the often-overlooked perspective of children struggling with being overweight.

About Dr. Robert A. Pretlow

Dr. Robert A. Pretlow is a pediatrician and childhood obesity specialist. He has been researching and spreading awareness on the childhood obesity epidemic in the US for more than a decade.
You can contact Dr. Pretlow at:


Dr. Pretlow’s invited presentation at the American Society of Animal Science 2020 Conference
What’s Causing Obesity in Companion Animals and What Can We Do About It

Dr. Pretlow’s invited presentation at the World Obesity Federation 2019 Conference:
Food/Eating Addiction and the Displacement Mechanism

Dr. Pretlow’s Multi-Center Clinical Trial Kick-off Speech 2018:
Obesity: Tackling the Root Cause

Dr. Pretlow’s 2017 Workshop on
Treatment of Obesity Using the Addiction Model

Dr. Pretlow’s invited presentation for
TEC and UNC 2016

Dr. Pretlow’s invited presentation at the 2015 Obesity Summit in London, UK.

Dr. Pretlow’s invited keynote at the 2014 European Childhood Obesity Group Congress in Salzburg, Austria.

Dr. Pretlow’s presentation at the 2013 European Congress on Obesity in Liverpool, UK.

Dr. Pretlow’s presentation at the 2011 International Conference on Childhood Obesity in Lisbon, Portugal.

Dr. Pretlow’s presentation at the 2010 Uniting Against Childhood Obesity Conference in Houston, TX.

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