Do These Genes Make Me Look Fat?

In “On the Road to Genetic Architecture,” we observed that genome-wide association studies, or GWAS, are the wave of the future. The newest research indicates that when things go haywire in the human body, the trouble is rarely traceable to a single gene. No, that would be too easy.

Up until quite recently, it seemed evident that…

[…] inherited genetic disorders that cause obesity are individually very rare, they may be involved in up to 10% of cases of severe childhood obesity.

Scientists believed and hoped that the key to obesity might be monogenic. Given the successes of epidemiology, it was easy to maintain that mindset. Keep children away from lead, and lead poisoning is no longer a problem. Neutralize the polio virus and, voilà! No more polio.

Thought experiment: What if, instead of a vaccine, polio could only be prevented by assuring that each child would eat figs for breakfast, avoid shoelaces longer than 22″, wear necklaces made of copper links, prefer reading graphic novels to playing video games, and have a grandparent who played trumpet? All those conditions could be met.

Creating a world without crippling paralysis would be difficult, but doable. Presumably, through intense education, governmental intervention, and ambitious social programs, children could be saved.

The basis of knowledge

But take a step back. Where does such information come from? To create the knowledge base for that anti-polio protocol, billions of people would have to be interviewed about every aspect of their lives. Tons of facts would have to be accurately recorded and safely stored. Thousands, if not millions, of people would need to be trained, and devote their lives to collating all this data and making sense of it.

How long would it take to figure out that the only people who never got polio were the ones who started their days with figs, kept their shoelaces short, wore the copper, preferred the graphic novels, and had trumpet-playing ancestors? What a mind-boggling, gargantuan task!

Figuring out the genetic basis of obesity is a lot like that. Complex diseases arise from a polygenic collaboration of SNPs (single nucleotide polymorphisms) whose concerted effort defines “multi-factorial” in a previously unimagined way. Keeping track of the relationships is nightmarishly complicated.

The work that has been done on genetic architecture could never have been undertaken without computers that can do a whole lot of staggeringly complex math very quickly. To keep up with recent developments, ideas have had to change rapidly too.

The simpler days

A gene known as FTO might have fooled the scientific community into thinking the secrets of these connections would be easier to crack. It has been more than a decade since obese people were found to have variants of the gene. A few years later, MIT and Harvard researchers found that a faulty FTO switches on two other genes “which have been identified as the ‘master controllers’ of the process of thermogenesis as they can prevent the process in which energy is turned into heat, meaning it is instead stored as fat.”

As described by journalist Louella-Mae Eleftheriou-Smith:

Energy balance is a conglomerate of traits, such as genes, behavior, diet, and metabolic factors, and each influences the other. Complex genetic factors among these contribute to individual difference in the development of obesity. Gene–environment interactions play an important role in the etiology of obesity.

In other words, the scientific community began to suspect, if they had not already, that the convenient “energy balance” formula was not as straightforward as they would have preferred.

The Introduction to a 2016 study gives the example of how “several genes expressed in the hypothalamic region are involved in the regulation of appetite,” and explains how the so-far strongest genome-wide association relating to obesity is located in the FTO gene and its SNPs. It was found that FTO variants also linked up with non-alcoholic fatty liver disease, colon cancer, pancreatic cancer, and the long-term outcomes of bariatric surgeries.

In 2016, a meta-analysis that dipped into the medical histories of 47,000 children of European ancestry, in what was then the largest study of whatever connects genetics with a high childhood BMI. It confirmed a lot of was already known or suspected, and identified three new genomic regions or “novel loci” associated with the problem.

(To be continued…)

Your responses and feedback are welcome!

Source: “New genetic cause of severe obesity and diabetes,”, 07/02/15
Source: “Scientists discover how ‘obesity gene’ works when faulty, giving new hope for finding cure,”, 08/24/15
Source: “Genetic Associations of Obesity: The Fat-Mass and Obesity-Associated (FTO) Gene,”, 01/28/16
Source: “New gene variants found in childhood body mass index,”, 03/10/16
Photo credit: Sandra Cohen-Rose and Colin Rose (colros) on Visualhunt/CC BY-SA

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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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