by Dan Zhu

If geneticists are asked what drives them to do the hard work in research, the answer can vary from one geneticist to another. However, for many of them there is probably a common intellectual reward they find particularly worth striving for, something that can be called the “Ah-ha” moment.

The human genome contains about 3 billion base pairs of DNA and many of these base pairs are variable. Although most genetic variations do not bring about any observable or phenotypic changes, some of them are important in determining personal traits that make each of us unique, and others cause or predispose us to  deleterious health effects. Human geneticists have been searching for genetic variations that contribute to various health conditions.

Over the short history of human genetics, there have been many exciting “Ah-ha” moments, which come when an association of a genetic variant with a condition makes sense, because the gene is known to play important roles in biological functions that are disrupted by the disease. For example, an “Ah-ha” moment arrived when mutations in a gene involved in inner ear development were found in hearing loss patients but not in their unaffected relatives. That was a home run.

There have been many “Ah-ha” moments for geneticists who study obesity. Mutations causing obesity have been repeatedly identified in a handful of genes that are involved in hypothalamic regulation of food intake and energy expenditure (PMID 18775361). However, these mutations can only account for a very small number of obesity patients. In these patients, who are often morbidly obese, a single mutation gives rise to the condition and, therefore, these patients are considered to have a monogenic form of obesity.

There have been many “Ah-ha” moments for geneticists who study obesity.

Most people who are obese do not have mutations that cause monogenic forms of obesity. This has posed a puzzle for geneticists because it has long been estimated that somewhere between 40 to 90 percent of the variation in body mass index (BMI) among the general population is inherited (PMID 20381893). A strategy called genome-wide association study (GWAS) has been employed to investigate the genetic basis of this unexplained effect. In a GWAS, hundreds of thousands of genetic variations across the genome are tested simultaneously to identify variants associated with the disease or trait in question. This method aims to discover genetic factors that have smaller effects than monogenic mutations. In order to draw statistically robust conclusions from these small genetic effects, GWAS typically need large sample sizes.

GWASs are hypothesis-free, which means that they search not only in the genes with known functions but also in genes about which nothing is known.

As soon as the GWAS strategy was applied in obesity research, an uncharacterized gene called FTO (now called fat mass and obesity associated) seized everybody’s attention (PMID 17434869, PMID 17658951). After analyzing genetic data from tens of thousands of participants, the initial GWA studies found that variations within one segment of the FTO gene were associated with BMI and other obesity-related traits. This association was quickly replicated in many other studies (PMID 18373508).

The importance of the FTO gene is reflected in many parts of our Pathway Fit® report. FTO variants are tested for satiety and weight loss response to exercise, and they are also essential in calculating the Obesity Index and in making our diet recommendation.

The identification of FTO in 2007 as an obesity-related gene was the first successful story in the search for the genetic basis of common forms of obesity.  However, this did not constitute a typical “Ah-ha” moment for geneticists, because at that time nobody had a clue how FTO affects a person’s body weight. At the time when the GWAS results were published, the only knowledge about its function came from a related gene in mice. The mouse Fto gene is part of a large region that is deleted in a mutant called Fused toes (Ft) (PMID 10501967, PMID 11956760). The Ft deletion caused a variety of abnormalities, but their relevance to body weight was not clear.

The importance of the FTO gene is reflected in many parts of our Pathway Fit® report. FTO variants are tested for satiety and weight loss response to exercise, and they are also essential in calculating the Obesity Index and in making our diet recommendation.

Since the genetic association was identified, major efforts have been made to understand the function of FTO (PMID 19924617), which we now know is a gene that is expressed in many tissues in the body. In mice, the level of FTO expression in the hypothalamus decreases in response to fasting, suggesting that FTO has a role in hypothalamic regulation of energy balance and eating behaviors. Mice genetically engineered to overexpress FTO show increased food intake, which leads to obesity (PMID 21076408). The function of FTO in the central nervous system is also supported by the finding that children carrying an obesity-associated FTO variant have increased energy intake (PMID 19073975). Besides its effects in the brain, the FTO protein may also have functions in other tissues where it is also expressed (PMID 19924617).

Many questions need to be answered until we can fully understand the association of the FTO variants with body weight. It is even possible that the association reflects the effects of unknown changes in the gene next to FTO. As many genes of unknown functions are being uncovered by GWAS, the scientific problems are becoming more complex and the tasks more challenging. While some might long for the old days when the problems were simpler and the “Ah-ha” moments more frequent, geneticists can take pride in the fact that they are pioneers blazing trails into uncharted territory. In fact, if it were not for GWAS, it would not have occurred to us that the FTO gene was a key that could unlock some secrets about obesity.