Researchers Look To The Future Of Obesity Genetics

ErinC — Thu, 18 Jun 2009 21:46:33 +0000

It’s no secret that obesity rates are rising — quickly. Between 2000 and 2005 the prevalence of obesity rose by 24%. Extreme obesity increased by more than 50%. If current trends continue, more than half of all Americans will be clinically obese by the year 2030.

Rapid changes in the prevalence of a disorder suggest that environmental rather than genetic factors are to blame. But scientists know from twin and adoption studies that body mass index (BMI) is highly heritable. So which is it: nature or nurture?

As with many aspects of human health, it’s both. Some people have the bad luck to have inherited genetic variations that together with the modern environment – sedentary jobs and hobbies, easy access to calorie-dense foods – create the perfect storm for the onset of obesity.

Changing the environmental factors that lead to obesity in some people seems simple enough – more exercise, less food. But public health campaigns touting these commonsense fixes have had little effect against the obesity epidemic. By understanding the genetic aspects of obesity, and how they interact with the environment, scientists may be able to develop more effective treatments and prevention strategies.

In the July issue of Nature Reviews Genetics Andrew J. Walley of Imperial College London and colleagues review the current state of obesity genetics research. While much progress has been made, the authors make it clear that there is still a long way to go, as the genes identified thus far explain only a tiny fraction of the total genetic component of obesity.

One key to future advancements in obesity genetics research, say Walley et al., lies in improvements to current genomewide association study (GWAS) methods.

First, the authors recommend that researchers focus on recruiting extremely obese people for their studies to increase the likelihood of finding genes with large effects. They also suggest that scientists should stop using BMI as their primary measurement of obesity. While simple and cheap, this method does not take fat distribution or the ratio of fat to muscle into account. There are more sophisticated methods, such as CT scans, MRI scans and ultrasound imaging, as well as machines that use air displacement to measure body volume and weight and can calculate fat and fat-free body mass. Technological advances that will reduce the costs associated with genotyping, and ultimately genetic sequencing, are also needed so that larger numbers of subjects can be studied.

Beyond these improvements to current GWAS methods, Walley et al. say studies of more than just common variations are needed. They suggest that investigations of rare SNPs, copy number variations (duplications, insertions and deletions of DNA) and inherited changes that don’t affect the actual DNA sequence will be needed to fully understand the genetics of obesity.

There are several competing theories about the overall biological basis of obesity. Some suggest that obesity is a disorder of energy balance in the body, while others think regulation of the growth of fat cells is the key. Still others think obesity may be due to defects in the neurological control of appetite and food intake. Continued advancements in understanding the genetics of obesity will help scientists tease these theories apart, and hopefully lead to a healthier future.

(23andMe customers can check their data for a SNP in the FTO gene in the Obesity Research Report. So far, this is the genetic variant most strongly associated with the risk of obesity. There is also an Obesity Preliminary Research Report.)

Needles in a Haystack

massie — Thu, 31 Jul 2008 22:25:52 +0000

Even as the genetic studies on schizophrenia released this week illustrate our progress toward the ultimate goal of personalized medicine, they also bring to mind the challenges that still lie ahead.

All three studies focus on identifying the genetic bases of schizophrenia, a mental disorder characterized by hallucinations, delusions and the decreased ability to plan and organize. These symptoms typically manifest during a patient’s late teens or early 20s.

One study led by Cardiff University researcher Michael O’Donovan identified single nucleotide gene variants (SNPs) associated with schizophrenia. As detailed in the journal Nature Genetics, the researchers started with 12 variants, narrowed the list to six after replicating the tests on several thousand study participants and finally identified three SNPs associated with the disease.

Unfortunately, the variant ultimately found to have the strongest association with schizophrenia — rs1344706 — is not included in 23andMe’s database. Yet the SNP’s effects are so small — it increases the chances of schizophrenia by only about 12 percent among people who have the higher risk version — that it offers limited information.

The other studies — one from the International Schizophrenic Consortium and one from deCODE and the SGENE Consortium — which appear in the journal Nature opted to look for genetic associations by checking copy number variants, DNA segments with deletions or duplications that can be inherited.

One group found three deletions — one on chromosome 1 and two on chromosome 15 — that showed up in a few dozen people out of thousands sampled and were more common among people with schizophrenia. The other group identified two of those three deletions. They also found that people with schizophrenia tend to have more rare copy number variants — both duplications and deletions — in their genomes compared to people without the disease.

“This work opens up an entirely new way to think about schizophrenia and eventually will suggest new avenues for researching effective therapies for the sake of patients and families suffering from this terrible disorder,” said International Schizophrenic Consortium member and study co-author Pamela Sklar in a statement.

One of the frustrations schizophrenia researchers have encountered is that while the disease is fairly common — affecting one percent of Americans — the genetic basis of schizophrenia has been difficult to pinpoint. One as-yet unsolved mystery is how the disease, which has a high degree of heritability, is as prevalent as it is when correlated with the fact that people who have schizophrenia and other similar mental disorders have fewer offspring.

These studies suggest that very rare gene mutations might play more of a role in the disease than had previously been supposed. That’s valuable information for scientists, and may explain why the genetics of schizophrenia have been so difficult to figure out. But it also suggests that it will take much more research to understand the genetic risk factors underlying schizophrenia than many other diseases.

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Researchers Look To The Future Of Obesity Genetics

Needles in a Haystack