Summary: Researchers identified several common genetic variants involved in obesity, as well as new genetic regions involved in severe obesity and healthy thinness.
Source: University of Cambridge.
In the largest study of its kind to date, Cambridge researchers have looked at why some people manage to stay thin while others gain weight easily. They have found that the genetic dice are loaded in favour of thin people and against those at the obese end of the spectrum.
More than six in ten adults in the UK are overweight, and one in four adults is obese. By age five, almost one in four children is either overweight or obese. Excess weight increases the risk of related health problems including type 2 diabetes and heart disease.
While it is well known that changes in our environment, such as easy access to high calorie foods and sedentary lifestyles, have driven the rise in obesity in recent years, there is considerable individual variation in weight within a population that shares the same environment. Some people seem able to eat what they like and remain thin. This has led some people to characterise overweight people as lazy or lacking willpower.
With support from Wellcome and the European Research Council, a team led by Professor Sadaf Farooqi at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, established the Study Into Lean and Thin Subjects – STILTS – to examine why and how some people find it easier to stay thin than others. Studies of twins have shown that variation in body weight is largely influenced by our genes. To date studies have overwhelmingly focused on people who are overweight. Hundreds of genes have been found that increase the chance of a person being overweight and in some people faulty genes can cause severe obesity from a young age.
Professor Sadaf Farooqi’s team were able to recruit 2,000 people who were thin (defined as a body mass index (BMI) of less than 18 kg/m2) but healthy, with no medical conditions or eating disorders. They worked with general practices across the UK, taking saliva samples to enable DNA analysis and asking participants to answer questions about their general health and lifestyles. It is thought to be the only cohort of its kind in the world and the researchers say that the UK’s National Institute for Health Research – the National Health Service’s research infrastructure – strongly enabled and supported their research.
In a study published today in the journal PLOS Genetics, Professor Farooqi’s team collaborated with Dr Inês Barroso’s team at the Wellcome Sanger Institute to compare the DNA of some 14,000 people -1,622 thin volunteers from the STILTS cohort, 1,985 severely obese people and a further 10,433 normal weight controls.
Our DNA comprises of a sequence of molecules known as base pairs, represented by the letters A, C, G and T. Strings of these base pairs form genetic regions (which include or make up our genes). Our genes provide the code for how our body functions and changes in the spelling – for example, a C in place of an A – can have subtle or sometimes dramatic changes on features such as hair colour and eye colour but also on a person’s weight.
The team found several common genetic variants already identified as playing a role in obesity. In addition, they found new genetic regions involved in severe obesity and some involved in healthy thinness.
To see what impact these genes had on an individual’s weight, the researchers added up the contribution of the different genetic variants to calculate a genetic risk score.
“As anticipated, we found that obese people had a higher genetic risk score than normal weight people, which contributes to their risk of being overweight. The genetic dice are loaded against them,” explains Dr Barroso.
Importantly, the team also showed that thin people, had a much lower genetic risk score – they had fewer genetic variants that we know increase a person’s chances of being overweight.
“This research shows for the first time that healthy thin people are generally thin because they have a lower burden of genes that increase a person’s chances of being overweight and not because they are morally superior, as some people like to suggest,” says Professor Farooqi. “It’s easy to rush to judgement and criticise people for their weight, but the science shows that things are far more complex. We have far less control over our weight than we might wish to think.”
Three out of four people (74%) in the STILTS cohort had a family history of being thin and healthy and the team found some genetic changes that were significantly more common in thin people, which they say may allow them to pinpoint new genes and biological mechanisms that help people stay thin.
“We already know that people can be thin for different reasons” says Professor Farooqi. “Some people are just not that interested in food whereas others can eat what they like, but never put on weight. If we can find the genes that prevent them from putting on weight, we may be able to target those genes to find new weight loss strategies and help people who do not have this advantage.”
About this neuroscience research article
Funding: The research was funded by the European Research Council and Wellcome.
Source: Emma Shaw – University of Cambridge Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is in the public domain. Original Research: Open access research for “Genetic architecture of human thinness compared to severe obesity” by Fernando Riveros-McKay, Vanisha Mistry, Rebecca Bounds, Audrey Hendricks, Julia M. Keogh, Hannah Thomas, Elana Henning, Laura J. Corbin, Understanding Society Scientific Group , Stephen O’Rahilly, Eleftheria Zeggini, Eleanor Wheeler, Inês Barroso, and I. Sadaf Farooqi in PLOS Genetics. Published January 24 2019. doi:10.1371/journal.pgen.1007603
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[cbtabs][cbtab title=”MLA”]University of Cambridge”Slim People Have a Genetic Advantage When it Comes to Maintaining Their Weight.” NeuroscienceNews. NeuroscienceNews, 224 January 2019. <https://neurosciencenews.com/slim-weight-genetics-10636/>.[/cbtab][cbtab title=”APA”]University of Cambridge(2019, January 224). Slim People Have a Genetic Advantage When it Comes to Maintaining Their Weight. NeuroscienceNews. Retrieved January 224, 2019 from https://neurosciencenews.com/slim-weight-genetics-10636/[/cbtab][cbtab title=”Chicago”]University of Cambridge”Slim People Have a Genetic Advantage When it Comes to Maintaining Their Weight.” https://neurosciencenews.com/slim-weight-genetics-10636/ (accessed January 224, 2019).[/cbtab][/cbtabs]
Genetic architecture of human thinness compared to severe obesity
The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05×10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99×10-6, obese vs. controls p = 2.13×10-6 pBMI = 2.3×10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.