Genetics of Obesity #obsmuk chat 20/3/2019


Genetics of Obesity

 


Before we begin, let’s explain some of the terms we will be seeing a lot in this discussion. Genetics is the study of genes, and how characteristics can be passed on from one generation to the next. Genes are segments of DNA that contain information. Some genes hold the instructions for building proteins that influence our characteristics, like how we look or how we behave. Changes can occur to the sequence of genes that may affect their function. Some genes have a few different versions of sequence which are normal in the population (present in more than 1% of people), these are ‘polymorphisms’- for example human blood group type. When the DNA change occurs rarely (in less than 1% of the population) then we call it a ‘mutation’.



The prevalence of obesity has risen with increasing access to calorie-dense foods and a decline in energy expenditure; the ‘obesogenic environment’. However, if environment and behavioural factors were the only causes of obesity then we would not expect to see the variation in body weight that we do. Our genes determine which of us feels greatest hunger and so becomes obese, and who is less susceptible to our unhealthy environment so stays slim. From studying families and twins it is estimated that the heritability of BMI (how much of the differences in BMI we see in a population is down to genes) is between 40-77%. Some of the observations that support this are that the BMI of adopted twins is more similar to their biological parents than their adopted parents, and that identical twins (with identical DNA) raised in separate environments are likely to have more similar BMIs than non-identical twins or strangers.



Almost all the genes that have major effects on BMI work in the brain to control eating behaviour. Genetic causes of obesity can be split into two main types: monogenic (single gene) and polygenic (affected by many genes).



Monogenic forms of obesity are caused by a mutation in a single gene, and run in families in a similar way to disorders like cystic fibrosis or Huntington disease. These forms tend to be rare, very severe, and present from early childhood. Most of these mutations occur in appetite- and metabolism-regulating genes, and the genetic effects are strong. Some of the most well-known genes in which mutations cause monogenic obesity are:

·         Leptin (LEP)

·         Leptin receptor (LEPR)

·         Melanocortin receptor (MC4R - mutations in this gene are seen in about 1 in 20 severely obese children)

·         Pro-opiomelanocortin (POMC)

·         Proprotein convertase 1 (PCSK1)

·         Single-minded homolog 1 (SIM1)



In addition, at least 10% of children with severe obesity have chromosomal abnormalities which form part of a syndrome that includes developmental delay, such as Prader-Willi or Bardet-Biedl.



In the study of general populations, we look at forms of obesity where the genetic effects are less strong and inheritance patterns less clear. Polygenic forms of obesity are much more common than monogenic, and caused by a combination of variations (polymorphisms) in multiple genes. Each polymorphism plays a small role in causing obesity, but together they can significantly increase BMI. Genome-wide association studies (GWAS) in large populations can identify these high-risk variants. Genes in which polymorphisms can confer risk of obesity include:

·         Fat-mass and obesity associated gene (FTO)

·         Peroxisome proliferator-activated receptor g (PPARG)

·         Adiponectin (ADIPOQ)

·         Leptin (LEP)



In this chat we will discuss some of the genetic causes of obesity in more detail, and focus on what the research means for prevention and treatment.



The following questions will be addressed:



·         Genes have not changed over the last few decades, so why is obesity rising?

·         Can obesity with a strong genetic cause be prevented or do people just have to accept their fate?

·         How can I find out if I have a genetic cause of obesity?

·         How might identifying genetic causes of obesity influence treatment options?

·         Why is it important to understand more about the genetic causes of obesity?


Dr Olivia Szepietowski and Professor Alex Blakemore

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