Genetics of Obesity

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Genetics of Obesity
Family and twin studies. Impact of the environm
ent.

2
Obesity Family Studies

• multiple studies indicate that genetic factors
  account for a substantial portion of variation in
  human obesity
  
• heritability estimates of obesity are determined
  by comparing BMI correlations between related
  individuals
  
• if the correlation increases with the degree to
  which the two individuals share a common
  phenotype, this provides evidence that a persons
  genotype is an important factor governing their
  body weight
• BMI correlations for biological
  parent-offspring pairs 0.19 0.25
  
• BMI correlations for adoptive relative pairs
  0.06
  
• this illustrates a moderate genetic component

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Obesity Twin Studies

• BMI correlations for MZ twins 0.74
• BMI correlations for MZ twins reared apart
  0.62
  
• BMI correlations for DZ twins 0.32
• Heritability 50 - 90 (quite high.)

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Obesity Family and Twin Studies

• appreciating the importance of genetic
  variation as an underlying cause of obesity helps
  to dispel the notion that that obesity represents
  an individual defect in behavior
• these studies provide a rationale for
  attempting to identify the genes that participate
  in the development of obesity
  
• but, dont forget that GENES INTERACT WITH
  ENVIRONMENTAL FACTORS to control behavior

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Chromosomal Location of Obesity Genes

• What are susceptibility loci?
• common genetic sequence that is associated with
  a particular phenotype
  
• identified by large scale genome-wide searches
• more susceptibility loci have been identified in
  mice
  
• appears to be multiple susceptibility loci in
  humans

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• Single gene mutations can promote obesity in
  humans
  
• Mutation of the ob gene
• chromosome 6 in mice
• chromosome 7 in humans
• in humans, this mutation produces
• morbid obesity (early onset)
• increased appetite - hyperphagia
• inability to satiate
• low/undetectable levels of leptin
• hypogonadotropic hypogonadism
• leptin treatment reduces food intake
• and body adiposity

7

• Mutation of the db gene
• chromosome 4 in mice chromosome 1 in humans
• in humans, this mutation produces
• morbid obesity (early onset)
• increased appetite
• inability to satiate
• very high levels of circulating leptin
• hypothyroidism
• growth retardation
• do not respond to exogenous leptin

8

• Mutation of the agouti gene
• chromosome 2 in mice chromosome 2 in humans
• 2 children have been identified with this
  mutation
  
• phenotype
• obese (early onset)
• greatly increased appetite
• inability to satiate
• yellow pigmentation
• possible therapeutic intervention treat with
  MC4-R agonists