Sunday, May 26, 2013

Is There a Genetics of Human Obesity?

There seems to be a persistent search for the genetic basis of human obesity. Again the basic fact of  life is that 3500 kcal equal one pound of body weight. So if you burn 2000 kcal per day and consume 2350 per day you gain one pound in ten days. That is a simple law. Genes or no genes.

Now in a recent NYAS paper the authors search for the elusive cause, neglecting the apparent truth. They state:

Although a number of significant findings have been made, it appears that very little of the apparent heritability of body mass index has actually been explained to date. New approaches for data analyses and advances in technology will be required to uncover the elusive missing heritability, and to aid in  the identification of the key causative genetic underpinnings of obesity.

In the past two decades, family studies and animal models have helped us to identify many genetic
events associated with obesity. Subsequently, GWAS have driven the transition from primarily studying monogenic traits to ones of a more polygenic nature. GWAS have also revolutionized the genomics of obesity field, in that it offers an unbiased approach to uncover novel common genetic variants contributing to the pathogenesis of obesity.

Despite these great advances, the combined results of linkage, candidate gene, and GWAS approaches have explained very little of the variance in BMI, suggesting that there are still many  genetic findings to be made, most likely being rarer variants exhibiting small effects. In order to fully characterize this missing heritability, larger and larger sample sizes are going to be required to improve statistical power. New technologies, such as next generation sequencing, will help us  identify these elusive obesity-associated variants, particularly as the price of these techniques  continues to drop. 

In addition, most of variants that capture the association with obesity from current  GWAS are not themselves causative. As such, how to move from association to causality remains a  big challenge for common complex diseases like obesity. Therefore, we need to develop new  approaches for analysis to characterize the true causative genes and perform functional studies to  determine their roles in obesity. Once at least some of these challenges have been mastered, we will  have a clearer picture of the genomics of obesity. This, in turn,will help us produce more efficacious  therapies and will guide us on the path to personalized medicine. 

Somehow the basic element of obesity is missed. How does a gene make you eat more? Perhaps you have a lower BMR but the equation holds for almost all humans. Why waste time on genes. One must tell fat people they are fat because they fail to control intake, it is their fault.