Calculating a gene x environment interaction in autism

And so what's missing is this gene environment interaction, right? Which we know is there.

We haven't been able to quantify it or kind of define it, we know it's there.

The other problem I think that people come up with when they think about environmental factors is that the environment is so variable, right? So you can have medical exposures, toxic exposures, you can have contextual factors as the environment.

And then the genetics are so complicated because you have the rare variants, which are those single genes that if you have one of these gene variants, then you have a very high likelihood of having an autism diagnosis.

And we think about 20% of people with autism have one of these.

And then there's a huge chunk of genetics that is genetic, but it's not one gene.

It's combined variation in multiple genes.

And that's the polygenic.

And there is something to define that that isn't like a gene.

It's something called the PGS score.

So can you explain and make sure that I got the difference between common variation and rare variation right? Not that we only see gene environment interactions with common variants or rare variants, but for the purposes of...

Trying to demonstrate something you got to pick.

So why did you pick polygenic and what is a polygenic risk score? Sure.

So I'll start with what's a polygenic risk score.

So what that is, is, yeah, it's really meant to be, as you said, across the genome, right, or our DNA sequence.

There are certain places in there that increase liability for autism.

Okay.

But a small bit.

just a little bit for each one of those.

And so rather than studying each one individually, what we can do then is assess the sort of aggregate liability at these places in the genome as kind of a single number or a single score of how many of these genetic variants that influence your autism likelihood do you carry in your DNA sequence? And so we sort of count those up And we weight them by how much of an effect or influence they have on autism.

And that's what we call a polygenic score, is it's really the sum, right, of all those places in the genome that any individual carries.

And in addition, people can have these polygenic scores, right, or the sum.

And also, there can be rare variants as well.

And you can look at rare variants in combination with common polygenic variation and both of those interactions with environment and how they're expressed in different environmental contexts.

Yeah, and I will just add, like, you know, like before the era of genomoid association studies, which focused on studying common variant across the whole genome, for many diseases, including autism, I know breast cancer, I work a lot, genetics was mainly defined as a binary condition.