Biggest Gene Study Finds New Clues To Obesity, Apple Vs. Pear Shapes

You might think the link between genes and weight is simple: Fat tends to run in families, right? But as researchers tease apart the underlying genetics of body weight, it becomes ever clearer that it is a complex trait. Very complex, with ultimately perhaps hundreds of genes involved in what you see when you step on the scale.

Today, the biggest-ever study of the genetics of obesity, involving genetic samples from nearly 350,000 people, reveals dozens of new spots on the human genome that are involved with body weight and body shape, according to two papers (here and here) published in the journal Nature.

My dominant impression: The data tend to implicate the brain as a powerful influence on overall body weight, but point more towards hormones and the fat cells themselves as strong determinants of whether we're shaped like "apples" — with more upper body fat — or "pears," with more fat concentrated below the waist.

Dr. Joel Hirschhorn, of Boston Children’s Hospital, the Broad Institute and Harvard Medical School, leads the Genetic Investigation of Anthropometric Traits consortium, or GIANT, the friendly collaborative of hundreds of researchers around the world who contributed to the studies. Our conversation, lightly edited:

How would you sum up the findings that come out in "Nature" today?

We did a very large genetic study looking at two different kinds of obesity: Overall obesity measured by body mass index and central obesity — fat around the belly — measured by waist circumference and hip circumference. And what we found was that there are a lot of genes that influence both types of obesity, but, really interestingly, the types of genes that influence overall obesity are actually quite different than the types of genes that influence where the fat goes on the body.

Interesting. So what does that tell us?

That tells us that even though both types of obesity are bad for your health, that it may be very important to understand what kind of obesity you have, because if the biology is different, that means the way we can treat that obesity, or prevent it effectively, is probably going to be different for the two kinds of obesity.

So it may matter even more than we thought whether you’re shaped like an 'apple or a 'pear'?

That’s right. It matters both whether you're an apple or a pear and it matters just how big you are in general. But the way you get to be big in general is probably different than the way you get to be an apple or a pear.

So it's different pathways? Perhaps whole different mechanisms at work?

That’s right. The overall obesity seems to have more to do with what's going on in the brain, maybe controlling appetite or whether you get full or how quickly you get full. And the apple vs. pear seems to have more to do with your fat cells and hormones that your body makes, things like insulin.

So does all this translate into any action points for the general public?

We hope it will eventually, but the main goal of this study is to try to figure out what's going on in obesity. We've really been shooting in the dark with our attempts to treat and prevent obesity because we don't understand the biology. So what we hope is that this is going to be a long-term impact where, by understanding the biology better, we'll eventually be able to get better treatments and better prevention, or maybe even take the things that we do now that don't work so well and make them work better.

The fact that you've pinpointed dozens and dozens more genes involved in these processes, does that matter? How?

It does matter. Some people have gotten worried by the fact that there’s so many different genes and each of them plays a small role. But in a way that’s encouraging because each of those new genes is a potential clue to a new treatment, so this has opened up a lot of new doors to potentially discovering new treatments for obesity.

But obesity is largely about interaction between genes and environment, right?

It’s definitely both. It’s definitely genes and environment. We're looking almost entirely at the gene side in this study, but we and other people, now that we know some of the genes, we’ve started to look at whether that you're physically active, or what diet you eat — whether that matters more or less depending on your genetics. And there’s some hint that there’s a little of that going on.

What are the next steps that stem from these findings?

We’re going to continue to do genetics — we think we’ve got some of the genes but we haven’t gotten as many as we’d like, even in this very large study.

But I think the big next step is to try to figure out what these genes do, and then figure out how that can be used to develop better treatments, or help the treatments we already have work better.

So what's the total number of genes now linked to obesity at this point?

For Body Mass Index it's 97 different places in the genome, and for waist to hip ratio, it’s 49.

What might the total number of genes linked to Body Mass Index be?

I don’t think we have a good idea. By one way of doing the accounting, we’re only a small fraction of the way there, so almost certainly it’s going to be many hundreds of genes. But I think that as these studies get bigger and bigger, we’ll start hitting the same genes over and over again, so it's not going to be every gene in the genome.

Readers, thoughts? Questions?