Genetics of Obesity

Genetics of Obesity

Weight Watchers: How much you weigh depends on many metabolic pathways, brain signals that regulate appetite, and environmental factors such as your lifestyle and diet. At least some of this is coded by genes, but narrowing down which ones is like finding the proverbial needles in a haystack. There are millions of gene variants, known as single-nucleotide polymorphisms or SNPs (pronounced snips), between any two people, than can be read from a sample of DNA (from a cheek swab). A Genome Wide Association Study or GWAS (pronounced Gee-Wahs) compares gene variants between two groups of people, say skinny and overweight, to see if any particular variant is associated with a trait, like obesity.  If any particular SNP is significantly more frequent in obese people, compared to the skinny group, then that SNP could mark a gene associated with body weight.

The Manhattan Plot: Named for a city skyline rather than a Hollywood thriller, this scatter plot helps pinpoint the genetic variants associated with obesity. Each color represents a different chromosome, with the largest chromosome on the left, going down in size and ending with the X chromosome on the far right. Each colored dot is a SNP, and the higher it is on the vertical (y axis) the bigger the difference of that variant between the two groups. In this study, the most significant SNPs were on chromosome 16 (light gray dots), in a gene called FTO. In another study, researchers measured levels of the hunger hormone grehlin after a meal: in people with a high risk variant of the FTO gene, grehlin levels in the blood stayed high, instead of dropping to signal that they were full. FTO codes for an enzyme that alters chemical modification (methylation) on the RNA messages coding for many proteins. For more on FTO see the Wiki page ( 

The Thrifty Gene Hypothesis: In 1962, geneticist James Neel proposed that gene variants contributing to obesity may have been of selective advantage during ancient times of food scarcity. For example, mice with mutations in the Mrap2 gene gain more weight for the same number of calories consumed. Not to be outdone, biologist John Speakman countered with the Drifty Gene Hypothesis which suggests that the loss of threat from predators, about 2 million years ago, removed a key factor selecting against obesity! The biological battle of the bulge continues….

REF: A Genome-Wide Association Study on Obesity and Obesity-Related Traits.  Kai Wang et al., PLoS ONE

Image: From +BPoD


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58 Responses to Genetics of Obesity

  1. Brad Esau says:

    Terrific stuff, Rajini Rao .

  2. Kathryn Kure says:

    Not sure I’d like to buy a penthouse in your Manhattan – looks to be a bit draughty 😀

  3. Rajini Rao says:

    Thanks, Brad Esau !

    Kathryn Kure especially when it’s the P value that raises the roof like that 🙂

  4. Chad Haney says:

    Another great post Rajini Rao. Are you familiar with Dr. Tim Lightfoot’s (Texas A&M, I think postdoc at JHU) work about a so called “couch potato” gene? On NPR he talked about how some people are predisposed to not be active, i.e., workout. He also talked about some of his genetic research on professional athletes. Fascinating stuff.

  5. Rajini Rao says:

    Chad Haney , had not heard of the couch potato gene, haha! Coincidentally, a quick search revealed that it is the same FTO gene I used as an example in this plot. “The latest findings show that participants with a certain variation of the gene called the FTO gene have a harder time staying with an exercise program than those participants with an alternate form of the gene. Those with the particular variation feel exercise is difficult and unpleasant.”

  6. Rajini Rao says:

    Checking on J. Timothy Lightfoot now..he was indeed at Hopkins and I’m trying to figure out whom he trained with, Chad Haney .

  7. Chad Haney says:

    I’ll read that later Rajini Rao (I’m just finishing lunch). The other aspect of Lightfoot’s work is that he’s having trainers rethink the schedule of training for some athletes. He was saying that for some genetic profiles, those people can only do X amount of activity per day. So if you train say 3 hours and need to do your game the same day, you could have eaten into that persons allotment of activity for the day. One example he gave is that Michael Phelps plays a lot of video games during his downtime; what we would think of as couch potato activities.

  8. Rajini Rao says:

    I like his theory, Chad Haney . Anything to avoid exercising 🙂 Enjoy lunch. 

  9. Chad Haney says:

    It makes sense to me for athletes like Phelps and sprinters. They probably can only have bursts of activity so many times. No sense wasting that on too much training.

  10. Marta Rauch says:

    Rajini Rao excellent topic, interesting information. Thank you for a great post 🙂

  11. Rajini Rao says:

    Marta Rauch , thanks for stopping by 🙂

  12. Rajini Rao says:

    Gnotic Pasta , have you heard of the myostatin gene? It keeps muscles from becoming too large. People with mutations in this gene develop body builder muscles! It was discovered in a German family where both parents are body builders and their child had amazing muscle size and definition. I have colleagues studying this as potential treatment for muscle wasting diseases. 

  13. Rajini Rao says:

    I suspect that you are genetically incapable of being a couch potato, Gnotic Pasta 🙂

  14. Chad Haney says:

    Rajini Rao he’s a stud, not a spud.

  15.  “the loss of threat from predators, about 2 million years ago, removed a key factor selecting against obesity” …. security and peace of mind causes obesity 🙂 

  16. Rajini Rao says:

    ROFL. I’m not going to start on the couch jokes either, Chad Haney .

  17. Rajini Rao says:

    prabhat parimal , that’s why Julius Caesar said, 

    “Let me have men about me that are fat,

    Sleek-headed men and such as sleep a-nights.

    Yon Cassius has a lean and hungry look,

    He thinks too much; such men are dangerous”.


  18. Chad Haney says:

    There are chaise lounges and then there are chase lunges.

  19. Rajini Rao says:

    Hah! Don’t whet his appetite, Chad Haney .

  20. If Man hatten plotted for obesity then who did?!

  21. affected neuro cell for jacobs diseases: origin is prion /as a protein playing OR game betwen neurotrasmetr and electric charge /+or – disturbing arn and enyme neuronal system  hes invisible like ur meduse in the sea; scan it look how its physical dynamic in hour brain my humble postulat….  if u like couscous ill send you my mothercouscos so tasty than you show  6month ago

  22. Chad Haney says:

    That’s the weirdest bot I’ve seen.

  23. Gnotic Pasta I saw a Silverback Gorilla in a German zoo he was eating a twig and there was zero evidence of a fitness center and yet I think he had zero body fat and a v-shape body. Genetics do matter.

  24. Yin Huang says:

    And of course, who could forget the Shifty Gene Hypothesis, wherein genes collude to lie about which ones actually control obesity.

  25. Adit Morey says:

    Comparison of difference in genetic traits is indeed very revolutionary. A combination of statistics and genetics is needed. The graphic representation of the genetic variations between obese and thin groups is a good example of application of mathematics to life sciences. Also, the Manhattan plot is very colourful representation.

  26. Rajini Rao says:

    Yin Huang , sounds legit 🙂

    Adit Morey , I expect there to be increasing demand for biostatisticians as whole genome sequencing and SNP analysis becomes routine.

  27. Adit Morey says:

    I believe in the near future, sequence for the entire genome will be stored in super-computers.

  28. Rajini Rao says:

    Adit Morey , actually, I think we could carry our own genome data on a personal card! 

  29. Adit Morey says:

    Yeah, might become a reality one day.

  30. Adit Morey says:

    I never liked biology.I had dropped the subject after my 10th. But your posts related to biology (genetics, for example) are really informative and interesting.

  31. Rajini Rao says:

    Adit Morey , thank you for that feedback, it helps me write 🙂

  32. Stuti S A I says:

    Very interesting article. Thank you.

  33. Rajini Rao says:

    Stuti S A I , you can always blame your genes 🙂 I especially liked the “couch potato” gene that was mentioned in a comment above. 

  34. NEY MELLO says:

     Rajini Rao  Well..well… Sure Sure 😀 :D…….So there was a mass genetic mutation affecting hundreds of millions of Americans,exclusively in the USA since the late 70s when the majority  in the USA  was actually healthy and vibrant and not obese or fat and diseased by 30 years of decadent  spiritually nihilistic, intellectually void,  materialism-worshipping lifestyle.

  35. Rajini Rao says:

    NEY MELLO I’m not exactly sure about your comment other than it was meant to be sarcastic 🙂 

    No one is saying that genes are the only underlying cause for obesity. See the opening sentence of this post. This type of research looks to why certain gene variants predispose people to obesity. There are syndromes in which single gene mutations result in vastly obese appearance, such as Prader Willi syndrome, Bardet Biedl syndrome, etc. These are rare genetic disorders, but they are a dramatic demonstration of the role of genes. 

    In case you want to understand the link between genetics and lifestyle, the “thrifty gene hypothesis” explains why obesity and diabetes rapidly increased among groups newly introduced to western diets and environments, including South Pacific Islanders, Sub Saharan Africans, Native Americans in the Southwestern United States, and Inuit. e.g., see this news story about Micronesians :

    The two scholarly reviews below discusses pros and cons of such theories.

    Prentice AM, Hennig BJ, Fulford AJ (November 2008). “Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release?”. Int J Obes (Lond) 32 (11): 1607–10. doi:10.1038/ijo.2008.147. PMID 18852700.

    Watve MG, Yajnik CS (2007). “Evolutionary origins of insulin resistance: a behavioral switch hypothesis”. BMC Evol. Biol. 7: 61. doi:10.1186/1471-2148-7-61. PMC 1868084. PMID 17437648 

  36. NEY MELLO says:

    Oh..I was just making an observation about today’s crisis of conscience and denial of decadence in American lifestyle choices. If we as Americans continue to subscribe to excessive gluttony and self-handicapping  as a family value, we are done as a nation… However there are signs that people are waking up form 30 years of couch coma induced by the  massive gluttony and binge drinking  frenzies of the last 20/30 years…So there is actually hope in sight…

  37. NEY MELLO says:

    and… my apologies! if I was a bit off-topic here!  😀 I promise to apply my commentary more topically next time!  😀 😀

  38. Rajini Rao says:

    NEY MELLO , not at all! I get the sense of what you were saying: after all, we all know that there is an epidemic of obesity in the US. My response is that there are certain genetic predispositions that make us vulnerable to this lifestyle…some of us more than others.  

  39. Chad Haney says:

    The key is that Rajini Rao is discussing predispositions not destiny. The genetics don’t sweep lifestyle choices under the rug. They just help us understand the extreme cases and what we can and cannot do.

  40. NEY MELLO says:

    Rajini Rao  Yes quite so…I can’t dispute that.

  41. Rajini Rao says:

    Chad Haney , that’s exactly right! Sometimes I get caught in my own verbiage 🙂

  42. Stuti S A I says:

    Rajini Rao I gotta fight them. The battle’s just begun!

    PS: I fall in the obese “class” 😉

  43. HI, Rajini,

    I think it is impossible not to gain weight because of, living in a gravitational field, we are always under a rain of particles interacting with the matter of our bodies,  creating entropy and undesired weight.

    Could this be proved?

  44. Mad B says:

    The idea of a ‘couch potato gene’ is very disturbing Rajini Rao Means these people are either cannibals (they eat chips) or became what they eat. More seriously, there was a BBC documentary on exercise [and genes], based on research by Professor Jamie Timmons team in Loughborough UK. Some people do not benefit from regular exercise, and this is .. genetic. They know how to test for that. The interesting thing is that they have thathighly intense ‘paddle till you die’_ 3-5mn exercise that produced surprising results. 



  45. Bill Collins says:

    Hold on. This is awesome science. However, is anyone doing research on these genes cross-indexed with gut bacteria??

  46. Rajini Rao says:

    Bill Collins , you are referring to emerging data that our gut bacteria contribute to obesity, right? But we don’t have population-wide data on gut flora yet, and a long way to go before we see links between our genes and specific microbes we carry. It’s a great idea. 

  47. Bill Collins says:

    Correct. (And thanks.) There’s fairly good evidence that said bacteria (the “bad” kind) multiply faster in some folks than others. I suspect a more complex picture than just “it’s your genes!”.

  48. Rajini Rao says:

    Perhaps more manipulatable, because our gut flora may be influenced by our diet, whether we have had antibiotics, for example. 

  49. Bill Collins says:

    Oh that’s a good point. Long term studies may be helpful. 

  50. Rajini Rao says:

    I’m watching the BBC video link on exercise and body weight that Madjid Boukri gave ( and it is fantastic. Simply looking at the fat floating in a blood sample 4 hours after a heavy meal is pretty sobering. Then there are the low responders, who don’t benefit as much from exercise as others. I like the idea of short, 1 min bursts of intense exercise 🙂

  51. Bill Collins says:

    HIIT is quite effective.

  52. How do I measure my grehlin level? If it’s possible.

  53. Lo Sauer says:

    What a  a super important topic. I will reshare this in a bit! Thanks Rajini Rao 

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