The Genetics of Obesity

1. The Genetics of Obesity

2. Learning Outcomes Identify the extent to which genes impact on a person becoming obese Discuss the difference between monogenic and polygenic obesity Identify some of the mechanisms by which genes influence a persons risk of becoming obese

3. Causes of obesity activity

4. Place these causes of obesity into the pyramid with most important at the top , some will have equal importance, some will be more important, some will have to be left out

6. The impact of genes on the risk of obesity Obesity is a complex multifactorial condition Determinants of obesity in an individual are not necessarily those that drive the increase in the population Extreme rise in prevalence indicates environmental rather than genetic causes However some individuals maintain a healthy weight despite an obesogenic environment Genetic differences between individuals account for 40 -70% of differences between individuals within populations (PHG Foundation, 2013)

7. Genes implicated in common obesity Research has found 50 loci to be associated with BMI, waist-hip ratio, percentage body fat and morbid obesity. Sizes of the established loci are small, and combined they explain only a fraction of the inter-individual variation in BMI Low predictive value therefore value in healthcare is limited (Day and Loos, 2011). Physical activity attenuates the BMI-increasing effect of some of the genes. Some genetic alterations have been identified as having an impact on how an individual might feel hungry or feel full following eating

8. One of the most commonly cited genes in relation to obesity is the FTO gene. FTO regulates the hormone ghrelin, which is an appetite hormone responsible for eating behaviour. Ghrelin stimulates hunger and increases food intake. Ghrelin reduces the sense of fullness after eating, causing further eating, and it also causes a preference for high fat foods.  High-risk variant of the FTO gene actually works in an epigenetic way by removing methyl groups from the ghrelin gene, causing it to produce more ghrelin (Karra et al., 2013).

9. 50% of the UK population are more likely to be obese because they have a particular variant of the melanocortin receptor gene MC4R (Chambers et al., 2008). The variant is more common in people of Indian-Asian ancestry which may partly explain high rates of obesity in this group. These gene variants also make people more likely to develop insulin resistance and type 2 diabetes.

10. Monogenic Obesity Rare single-gene disorders where severe obesity is the primary feature There are forms of severe, young-onset obesity caused by a defect in a single gene, although these are very rare in the population as a whole. Examples are deficiencies involving the hormones melanocortin and leptin which have a key role in regulating appetite and metabolism (Farooqi and O’Rahilly, 2007).

11. Rare genetic syndromes where obesity is an associated feature Some rare familial syndromes have obesity as one of many features, often associated with mental impairment, dysmorphic features and developmental abnormalities: e.g. Prader Willi syndrome, Alstrom syndrome and Fragile X syndrome (Farooqi and O’Rahilly, 2007).

12. References Foresight. Tackling Obesities: Future Choices. Project Report. London, UK: Government Office for Science, 2007. National genetics and Genomics Education Centre. Obesity and Genetics Factsheet. http://www.geneticseducation.nhs.uk/search/item/29-0029-genetics-and-obesity PHG Foundation. Genomics of Obesity: The Application of Public Health Genomics to the Prevention and Management of Obesity in the UK, 2013.