More genes identified that affect weight and stature

In addition to the 41 known locations on the human genome that are associated with the body mass index (BMI), another 56 gene loci have been found. This is the result of the so far largest international genome-wide association study (GWA) with over 339,000 people realized by the GIANT consortium.*

The scientists of this GWA-study presume that the frequent obesity-associated gene variants affect the BMI by about 21 percent. For the entire genome, they even presume a 40 to 70 percent influence. A further analysis of the entire genome in 224,000 people showed that 68 gene loci are associated with the distribution of body fat. Researchers at the University of Leipzig were involved in both GWA studies. The scientific journal nature reported about in its latest issue (12.2.15).

The distribution of adipose tissue on the body is crucial for the question how harmful overweight and an increased BMI are. People with an abdominal or visceral obesity have a higher risk to develop a type-2-diabetes or cardio-vascular diseases. In the data of the many participating research centers the scientists analyzed which gene variants were associated with higher or lower BMIs. Although all human beings are endowed with the same set of genes, there are differences in the sequence of their smallest parts, the nucleotides. These so-called gene variants have a big influence on the individual. “There is not the one obesity gene, but many different gene variants influencing BMI and body weight”, explains Peter Kovacs. He is Professor for the genetics of diabetes and obesity at the IFB AdiposityDiseases in Leipzig, he and his team participates in the GIANT consortium.

Interplay of genes and brain

Genes in the hypothalamus, hippocampus and the limbic system play a decisive role in obesity. These brain regions are responsible for metabolism, energy homeostasis, motivation, learning, memory and emotions. The FTO-gene (fat mass and obesity associated gene) which is most connected to adiposity is e. g. active in the hypothalamus and seems to influence eating behavior and nutrition. Further BMI-associated genes regulate the body’s glutamate, a neuronal transmitter whose activity is reciprocal with eating.  “This large study shows that genetics can more and more explain the heritability of obesity. Therapy approaches have however to focus on neuronal and metabolic activities, which are influenced by genes”, says Prof. Kovacs.

Individuals who show many BMI-relevant gene variants also have more genetic influences on metabolism. This could explain why an increasing BMI is associated with metabolic disorders. This meta-analyis which evaluated many different international research data also examined the effect of the 97 BMI-associated gene loci in distinct ethnicities. About 80 percent of these loci have in Africans a comparable effect as in Europeans. In East-Asians for even 90 percent of the gene loci this is true.

Genes influence where fat pads are

Since especially the fat distribution is telling how harmful overweight is, another GWA study of the GIANT consortium is important (Dimitry Shungin et al). This study proved that besides the 16 known gene loci associated with fat distribution there are 33 more gene variants that are connected to fat distribution independent of BMI or body height. Another 19 gene loci influence the BMI and the fat distribution. The GWA study came to these results by looking at the gene variations in probands with different waist- and hip circumferences. The ratio of waist to hip circumference is an important measure for abdominal obesity, the more unhealthy form of overweight. The ratio should be no higher than 1 in males and 0.85 in females.

Genes produce a feminine or masculine body shape

In contrast to BMI-associated genes, the ones connected to fat distribution have a bigger effect in women. 19 out of 49 gene variants which influence waist and hip circumference are more pronounced in females. These genes interact with gender specific hormones, so that in puberty and menopause the different fat distribution becomes most obvious. For the general fat distribution is determined by the gene set that emerges in the fertilized ovum.

The results of GWA studies form the basis for further research of biological mechanisms in body fat distribution and its consequences for health.  Only if scientists understand the mechanisms leading to more unhealthy visceral fat tissue they can find ways to interfere in these mechanisms and develop therapies. “The genetic research does not release us from our personal responsibility.  Independently from our individual gene profile enough exercise and a healthy nutrition remain the best ways to stay fit”, underlines Prof. Kovacs.

Doris Gabel

*GIANT: Genetic Investigation of Anthropometric Traits, an international research consortium, from the  IFB AdiposityDiseases Prof. Peter Kovacs, Prof. Matthias Blüher, Prof. Michael Stumvoll, Dr. Anke Tönjes and their teams participated in the GWAs.

Publications

Adam E Locke, Bratati Kahali, Sonja I Berndt, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 12.2.2015      doi:10.1038/nature14177

Dmitry Shungin, Thomas W Winkler, Damien C Croteau-Chonka, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 12.2.2015     doi:10.1038/nature14132

Also see the press release of the University of Michigan.