April 5, 201210:00 AM ET
Operator: Good morning ladies and gentlemen, and thank you for waiting. Welcome to the Obesity Genetics Press Call. All lines have been placed on listen-only mode, and the floor will be opened for your questions and comments following the presentation.
Without further adieu, it is my pleasure to turn the floor over to your host, Mr. Robert Bock. Mr. Bock, the floor is yours.
Robert Bock: Welcome to the National Institutes of Health. I’m Bob Bock, the Press Officer for the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This briefing will be on the forthcoming Nature Genetics paper, “A genome-wide association meta-analysis identifies new childhood obesity loci.” Our briefing is being held under the terms of the journal embargo, which lifts on 1 p.m. Eastern Daylight time, Sunday, April 8, 2012.
The study was conducted in part with federal funding administered through the National Institutes of Health, specifically the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Environmental Health Sciences, and the National Heart, Lung, and Blood Institute.
Now, if you’re still with me, our speakers today are Karen Winer, M.D., a Program Director in the NICHD Endocrinology, Nutrition, and Growth Branch, and study author Struan Grant, Ph.D. of the Division of Human Genetics and Molecular Biology at the Children’s Hospital of Philadelphia.
I would now like to introduce Dr. Karen Winer, who will begin our briefing.
Dr. Karen Winer: Bob, thanks very much. The substantial increase in the prevalence of obesity has created a global health crisis. In the U.S., the prevalence of childhood obesity has tripled in recent decades and related healthcare costs have quadrupled. The NIH has responded to this health crisis by addressing various aspects of this complex problem.
At the NICHD we focus on obesity research in childhood and also during pregnancy. Obesity is the result of a complex interplay among biological, behavioral, cultural, environmental, and economic factors.
Obesity is a key risk factor for a number of common metabolic disorders such as Type 2 Diabetes and cardiovascular disease. Other vital health consequences of obesity include Polycystic Ovarian Syndrome, infertility, obstetric complications, behavioral and mental health problems. All of these areas are considered highly relevant to our research programs at the NICHD.
Obesity is recognized as a highly heritable condition, but the underlying genetic factors in early onset common obesity have remained largely elusive. Although we have uncovered the genetic etiologies of several childhood syndromes associated with morbid obesity, the underlying genetic factors associated with common obesity, until today, have remained a mystery.
That brings us to Dr. Struan Grant’s recent findings. Dr. Grant was awarded NICHD funding four years ago to carry out a genome-wide study of common childhood obesity in order to facilitate the discovery of genes contributing to this condition. This has resulted in Dr. Grant and his colleagues at the Children’s Hospital of Philadelphia recruiting and genotyping the largest common childhood obesity DNA collection in the world.
Combining their dataset with other similarly collected datasets around the world under the umbrella of the Early Growth Genetics Consortium, Dr. Grant and his team have been able to identify a genetic etiology of common childhood obesity as compared to rare, syndromic -- extreme syndromic-- forms of obesity. Dr. Grant’s paper will be published in this -- this week in Nature Genetics with Dr. Grant as the senior author.
It is now my pleasure to turn this briefing over to Dr. Struan Grant so he can tell us -- tell you about his groundbreaking work. Dr. Grant?
Dr. Struan Grant: Thank you, Karen, and hello to everybody. Yes, the technique that we’ve been using for this approach is genome-wide association study -- studies, or GWAS for short. And in the last five years or six years, there’s been a technological breakthrough in terms of being able to scan the whole genome with no prior hypothesis to identify genetic variants underlying given traits. This has proved successful in many disease areas, but to date, there really has been very little success in terms of identifying robust genetic variants with childhood obesity until now.
As Dr. Winer pointed out, we have a program here at the Children’s Hospital of Philadelphia within the Center for Applied Genomics where we are collecting large numbers of samples of children, including individuals with childhood obesity.
To that end and thanks to the funding we got from the NICHD, we were able to genome-wide genotype them with these -- this new technology, these new arrays to be able to ask the question: are there identifiable genetic variants contributing to childhood obesity, or is it purely environmental? And certainly, with our results, we’re seeing there’s a clear genetic signature to childhood obesity.
In terms of us being able to get the maximum power to identify novel genetic variants associated with childhood obesity-- as opposed to genes that have already been identified in adult studies of body mass index and also to find variants that perhaps have been implicated in extreme childhood obesity-- we decided to form this early growth genetics consortium, or EGG, and combined 14 such datasets from the U.S., from Canada, from Europe, and from Australia. And that amounted to having five-and-a-half thousand of these children.
And how we defined the obesity was based on really the literature and what the general prevailing consensus in the field is that the upper fifth percentile, the 95th percentile of body mass index in children is an appropriate threshold for common obesity in children.
Obviously body mass index changes wildly over childhood, so using the absolute number for body mass index is challenging. Rather we look at zed (ph) scores, we look at deviation from the mean. And that’s very useful because it’s corrected for age and gender.
And we did that based on local growth curves for all the different 14 studies, and we then merged our datasets to see what we could find. And the first observation we saw was that some of the genes that had come up in the adult studies of body mass index, which were far larger, there were about a quarter of a million individuals in those adult studies, but we could see that some of those genes were operating very strongly in childhood and were contributing to childhood obesity, and we could readily pick them up in these five-and-a-half thousand kids that we had.
But in addition to that, we also wanted to discover novel genes that were not seen in adulthood, and to that end we took forward some novel signals and attempted to replicate them in nine further studies, also based in the same countries that I just listed. And that amounted to about two-and-a-half -- I’m sorry, 2,800 overweight kids and about 4,000 non-obese kids.
And I forgot to mention how we define non-obesity is that these kids were below the 50th percentile for body mass index, i.e., they’re in the leanest half of all these collections.
And so by combining the datasets from the 14 discovery and the nine replication, we robustly identified two new childhood obesity genes. Those genes are called OLFM4 and HoxB5. When we look at different age (inaudible), if we remove the under two year olds, for example, we find that those gene associations persist, but we also see evidence for two more genes.
And when we explore our two main signals in the more extreme obesity, which has been described previously, we did find that they continue to show association in that setting as well. But we find that they’re very strongly associated with regular common childhood obesity that we were investigating.
We also turned to look at the adult studies that had been previously published, and their data -- some of their data is available online, and we could simply query to see if our variants were operating as (inaudible), and it was clear that the adult studies were not going to detect these because they were somewhat weaker in the adult setting. So as a result, we conclude that these variants are conferring their risk early on in life and are really impactful in the first years of life.
And the interesting thing about the biology of the genes is that there is not much known about them in the context of obesity, so making them truly novel. When we look at the scientific literature, the only indications that we have is that they may be operating in the gut. So in terms of functional followup, in terms of how these genes confer risk for -- or confer susceptibility for-- childhood obesity, we would look probably in that tissue area to see how it was conferring the risk.
So as of -- so in summary, working as a collaborative effort driven by our cohort, funded by the NICHD, we have discovered two novel genes associated with common childhood obesity, and we see a clear genetic signature to childhood obesity showing that there is more than just an environmental component to this disease. Thank you very much.
Robert Bock: Okay, if -- our speakers are finished with their remarks, we can open it up to questions from the callers.
Operator: Certainly. The floor is now open for questions. If you do have a question, please press the number seven or the letter Q on your telephone keypad. Questions will be taken in the order they were received. If at any point your question has been answered, you may press seven or Q again to disable your request. Please hold while we wait for the first question.
The first question comes from Gina Kolata. Gina, please state your question.
Gina Kolata: I was wondering if you could explain to us how you go from a marker on the genome, which may have other genes near it, to identifying a particular gene? What makes you sure that these are -- these particular genes are the ones that are really being associated with childhood obesity?
Dr. Struan Grant: Yes. That’s a very good question, and you caught me using genetics shorthand. Effectively what we do when we do genome-wide association studies is that we get a strong signal, but we don’t believe for a moment that that is the causative variants. Rather, it is a tag. So it’s basically telling us that something in near vicinity, in the very close vicinity is an underlying causative variant contributing to the susceptibility to the disease.
So the shorthand that we use is we talk about the gene that the signal is in or closest to that gene, but we can’t rule out that it’s a neighboring gene to the closest gene. So we would require additional functional efforts to verify for certain that these are the two genes, but that’s how we generally report in genetics. It’s the closest gene to the signal.
Gina Kolata: Okay. But aren’t there other genes around and other things are noncoding? I’m just wondering because you seemed very certain when you spoke about these as being the -- possibly the causative factors of some childhood obesity.
Dr. Struan Grant: Well, the variant itself is capturing the disease association, the genetic association with the disease. No, I can’t be certain that these are the two genes, but these robust genetic variants reside near or within a gene.
But of course the mechanisms could certainly be noncoding RNA, it could be control of transcription, gene regulation, so the mechanism still has to be determined. So in terms -- as they say, in terms of reporting this-- we’re talking about geographical vicinity to a given gene.
Gina Kolata: Okay. Thank you.
Operator: Again, if you do have a question, please press seven or Q on your telephone keypad. Once again, that’s seven or Q. It appears that we have no further questions at this time.
Robert Bock: Okay. If there are no further questions, then we will go ahead and conclude our briefing.
Operator: Thank you. This does conclude today’s teleconference. We thank you for your participation. You may disconnect your line at this time.
Robert Bock: Thanks.
Dr. Struan Grant: Thank you.
Dr. Karen Winer: Thank you.
Back to news release.