Understanding polygenic score with Bugs Bunny

There is much confusion about what polygenic scores are and how to interpret them. There are even some excellent papers that criticized them (e.g., Wellenreuther and Hansson 2016), however it is fair to say that papers that preach in favor of polygenic scores are probably more popular. To clear some of the confusion around polygenic scores, I tried to come up with a simple explanation as to why everyone should know what polygenic scores are and why this is so useful in real life.

Imagine that Lola Bunny sent Bugs Bunny to the store to buy some vegetables, particularly carrots. Bugs Bunny carried out her instructions precisely (he wanted to eat!).

43028eb8afe88c60bb78a48b61cc0e4aUnfortunately, along the way he had a little incident with the440px-bugs_bunny.svg_

Road Runner. The Road Runner stole the bag of carrots and ran away. Bugs Bunny knew that he no one can catch the Road Runner, so he continued walking trying to think of a good way to explain the situation to Lola Bunny. He was too embarrassed to tell her the truth – that it’s all because of the Road Runner because he was afraid that she wouldn’t believe him (it’s a little difficult to see the Road Runner, most bunnies have never seen it). So he had to come up with something else. He handed the groceries to Lola.

– “Did you get everything” – “yes of course” – “Thank you, how lovely. Wait a second, where are the carrots?” – “They are right there.” – “Where?” – “There?” –

lolabunny

“I don’t see them” – “That’s because you are not looking hard enough!”

Bugs took out all the vegetables and lined

 them on the tables, “in each one of those vegetables, there is a little bit of carrot, because they share genetic similarity to the carrot, some more than other.”

Lola was confused. Did they genetically engineered a vegetable to taste like carrot in Looney Tunes? “Do any of those vegetables taste like a carrot?” she asked.

“Not at all.” He said.

“So what good are they?” she asked again

“Each vegetable contains a very small fraction of similarity to carrot, so if

you eat all of them, it’s like eating a carrot”

“A whole carrot?”

“No, maybe 3% of it.”

“So, let me get this straight, you didn’t buy a carrot, you got all these other vegetables – none of which looks, smells, or tastes like a carrot and I need to eat all of them to feel that I ate 3% of a carrot?”

“Now you are getting it!”

“Ha” was all that Lola could say because this made absolutely no sense to her. Bugs bunny anticipated another attack and quickly began citing the genetic literature. “This is how we’ll eat carrots from now on, this is the latest thing in genetics, this is how they explain why some bunnies are short, some are slow, and some have Schizophrenia.”

“Really? They found the genes to all those traits.” Lola began to feel that she was out of touch with the genetic progress in Looney Tunes.

“No, not one gene, much better – they found like hundreds and thousands of genomic mutations!”

“That does sound better. A lot better. So all these mutations, can they explain why those bunnies are short and all.”

“Of course, if you take all of them, then can also explain a very small fraction of the phenotype”

“So wait? What about the rest of it?“

“Well, that’s exactly the point!”

“The point of what? I am so confused!!!”

So, as you figured out by now, Bugs had no point. His argument was pointless. How can anyone aiming to explain the phenotype be happy with explaining a fraction of it? He counted on Lola stop arguing with him due to his superior knowledge in genetics, but Lola proved to be a hard nut to crack. So, he went back to the store. He bought carrots and some carrot-based snacks because all these arguments depleted his energy levels.

43028eb8afe88c60bb78a48b61cc0e4a

However, believe it or not, the Road Runner was waiting for him AGAIN and just like this time, the carrots were gone with the wind and Bugs had to exercise his brain once again because he couldn’t admit to Lola that he lost the carrots to the Road Runner again (this time, she threatened to cut his allowance)!

“Did you get the carrots?” – “Yes of course” – “Oh good, how lovely. Wait a second, where are they?” – “They are right t

lolabunny

here.” – “Where?” – “There?” – “I don’t see them. Are you playing stupid genetic games with me?” – “No, I am not here they are!”

And Bugs took our all the snacks he got and laid them on the table. “In each one of those bars, has a small fraction of carrot, so all together it’s one big carrot.”

“Really? How big?”

“About 1%”

“What the hell?! How can it be 1%? You said that there was 3% with all those vegetables and 1% now with all those carrot-based bars? Aren’t these snacks supposed to have more carrot?”

“Yes, but unfortunately, when you count carrots the way I do, and I know how to count them because, as you know, I am an expert on carrot-related matter, you don’t always get the same result when you do these counts. Sometimes, you don’t even get 1%, so consider yourself lucky.”

Lola didn’t feel lucky. She felt angry and annoyed. Not only she cannot make lunch, she also got two lectures in genetics that made no sense to her and two lines of products completely different from one another didn’t look or taste like carrot and, apparently, amounted to only a fraction of what makes a carrot a carrot, and then she had an idea.

“Can you arrange these vegetables and bars based on their similarity to carrot and give them weights? This way I’ll know how much each carrot I in each one and maybe use more of that item?” She thought that it was a clever idea, but Bugs was reluctant.

“No, because there is no way to know what made each thing to look like a carrot, there may be many reasons, like its history and population structure and so on, in fact, it may have nothing to do with carrot, just look like it.”

“So, why won’t you take these ones out?”

“Because I don’t know which one is real and which one is not”

“Well, what do you expect me to do?”

“Do what everyone else do, ignore it, just believe me when I tell you that they all have a little bit of carrot essence in them”

“You mean 1% of an essence”

“Yes, but remember again, if you are lucky! Which we are!”

Eventually Lola did cut Bugs allowance. She decided that she is not NIH and not RCUK and have no time for these nonsense. If Bugs cannot get her carrots, she’ll find someone else who can get them or at least come up with a much better excuse.

 

REFERENCES

 Wellenreuther M, Hansson B. 2016. Detecting Polygenic Evolution: Problems, Pitfalls, and Promises. Trends in Genetics 32:155-164.

 

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