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Researchers piece together gene, obesity and fat distribution puzzle

EU-funded scientists have identified 18 new gene sites that impact overall obesity and 13 new sites associated with distribution of fat. The researchers from Europe, as well as Australia, Canada and the US, used a near 250,000-strong sample to investigate genetic links with hu...

EU-funded scientists have identified 18 new gene sites that impact overall obesity and 13 new sites associated with distribution of fat. The researchers from Europe, as well as Australia, Canada and the US, used a near 250,000-strong sample to investigate genetic links with human traits. The findings of the two studies, published in the journal Nature Genetics, shed light on why some people are more susceptible to obesity while others are not. Part of the Genetic Investigation of Anthropometric Traits (GIANT) consortium, which comprises 400 experts from 280 research institutions worldwide, the scientists carried out a large-scale meta-analysis of genome-wide association studies (GWAS) providing insights on waist-hip ratio (WHR) and body mass index (BMI). 'Different people have different susceptibilities to obesity,' explains Dr Joel Hirschhorn from Children's Hospital Boston and the Broad Institute in the US, one of the senior authors of the obesity paper who was involved in both studies. 'Some don't rigorously watch what they eat or how much they exercise and still resist gaining weight, while others constantly struggle to keep their weight from skyrocketing. Some of this variability is genetic, and our goal was to increase understanding of why different people have different inherited susceptibility to obesity.' These studies succeeded in pinpointing genes that were never before suspected of influencing obesity. The results will help improve the categorisation and treatment of obesity in the future, according to Dr Hirschhorn. The overall obesity study investigated the genetic determinants of BMI, which is determined by measuring a person's weight in kilograms over height in metres squared. Data from 124,000 people from 46 studies uncovered 32 sites (of which 18 are new). The team found two novel variants, one of which is in the gene encoding for a receptor protein that responds to signals from the gut to influence insulin levels and metabolism, and another that is located near a gene known to encode proteins affecting appetite. 'One of the most exciting parts of this work is that most of the BMI-associated variants identified are in or near genes that have never before been connected to obesity,' comments Dr Elizabeth K. Speliotes from Massachusetts General Hospital and the Broad Institute, lead author of the BMI study and involved in both studies as well. 'Through this work we are discovering that the underlying biological underpinnings of obesity are many, varied and largely uncharacterised.' Their findings show that people with more than 38 BMI-increasing variants were about 15 to 20 pounds heavier than those who carried less than 22 such variants. The second study investigated associations between gene sites and fat distribution. Evaluating the genetic determinants of WHR of 77,000 people in 32 studies, and checking against data of more than 113,500 individuals in 29 studies, the researchers found 14 gene regions associated with WHR, adding 13 new sites. It should be noted that seven of the identified genetic variations have stronger effects in females than in males, hinting that they trigger some of the differences in fat distribution between women and men. 'By finding genes that have an important role in influencing fat distribution and the ways in which that differs between men and women, we hope to home in on the crucial underlying biological processes,' says Dr Cecilia Lindgren of the Wellcome Trust Centre for Human Genetics at Oxford University in the UK, a senior researcher on the WHR study, who was involved in both papers. The results in this study indicate that specific biological mechanisms play a role in regulating where the body stores fat. Genes that regulate cholesterol, triglyceride levels, and insulin and insulin resistance are associated with the regions impacting fat distribution. EU funding for the studies came from projects under Fifth and Sixth Framework Programmes (FP5 and FP6), specifically: EURO-BLCS (Biological, clinical and genetic markers of future risk of cardiovascular disease'), which was supported under the Quality of life and management of living resources budget line of FP5; as well as EUROSPAN (European special populations research network: quantifying and harnessing genetic variation for gene discovery'), MOLPAGE ('Molecular phenotyping to accelerate genomic epidemiology'), PROCARDIS ('A genome-wide mapping and functional genomics approach to elucidating precocious coronary artery disease'), and EURODIS ('Functional genomics of pancreatic beta cells and of tissues involved in control of the endocrine pancreas for prevention and treatment of type 2 diabetes'), which between them received over EUR 25 million from the EU under the 'Life sciences, genomics and biotechnology for health' Thematic area of FP6. The studies were also backed by an EU Marie Curie Intra-European Fellowship grant. European scientists that took part in the studies were from Austria, Croatia, Denmark, Estonia, Finland, Germany, Iceland, Italy, the Netherlands, Norway, Sweden, Switzerland and the UK.

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Austria, Switzerland, Germany, Denmark, Estonia, Finland, Croatia, Iceland, Italy, Netherlands, Norway, Sweden

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