1. Mindi Styn, PhD Obesity Researchers’ Journal Club September 16, 2010
Genetics and Obesity
Mindi Styn, PhD
Obesity Researchers’ Journal Club
September 16, 2010
By PresenterMedia.com

2. Genetics 101
Allele: One of the possible forms of a gene
U.S. Department of Energy Genome Programs :

3. Heritability of Obesity
In a study of > 4000 twin pairs heritability for weight was 78%, after 25 yr fup 81%
Adopted children have been found to have body sizes more similar to their biological parents than their adoptive parents
In a study of twins reared apart heritability of obesity was reported to be 70% for men and 66% for women
Twin studies have also shown high correlations within twin pairs for weight gain, weight loss and metabolic efficiency
Stunkard study – heritability for weight was .80
Bell C. Nature Reviews Genetics 2005

4. Heritability of Obesity
May change with age
In a large UK twin study heritability increased from .48 at age 4 to .78 at age 11
Shared environment decreases with age
Claire M.A. Haworth, Obesity 2008

5. Monogenic & Syndromic Obesity
Provide possible clues to the genetics of non-syndromic or “common” obesity
Monogenic Obesity
Severe, early-onset obesity related to genetic mutation
Mendelian pattern of inheritance (due to single gene)
Frequently disrupt leptin-melanocortin pathway
Identified mutations in leptin gene, leptin receptor, POMC (results in hyperphagia), melanocortin 4 receptor (MC4R)
Syndromic Obesity
Genetic mutation results in a set of symptoms that includes obesity
Example: Prader-Willi Syndrome
Extreme phenotypes
I. Sadaf Farooqi. Monogenic Obesity in Humans. Annual Review of Medicine 2005

6. Common Obesity Multiple factors and genes involved Energy intake
Energy expenditure
Energy storage

7. Associations with body size
Leptin (LEP)
Associated with decreased weight loss on a reduced calorie diet
G allele more frequent in obese and extremely obese women
Ghrelin (GHRL)
Leu72met minor allele is more common among children with a high BMI
Fat mass and obesity associated gene (FTO)
Strong association with BMI over a 25 year study, associated with increasing BMI
MC4R
2 recent GWAS supported association
Extreme phenotypes

8. Associations with body size
Dopamine Receptor 2 (DRD2)
PLCO Cancer Screening Trial, obese participants were more likely to carry the DRD2 TaqIA variant allele than were normal weight participants.
DRD4
Association with BMI among multiple study groups (black, hispanic, former smokers, with bulimia nervosa)
Brain Derived Neurotropic Factor (BDNF)
Associated with BMI and severity of disordered eating
Extreme phenotypes

9. Response to Treatment Uncoupling protein 2 (UCP2) gene
SNP appears to contribute to variation in response to sibutramine
131 obese patients from Taiwan
Individuals homozygous for major allele were unresponsive to treatment
Those with a minor allele had significant reductions in weight and fat mass compared to placebo
Extreme phenotypes
Hsiao TJ. Molecular Diagnosis & Therapy. 2010

10. Response to Treatment Hsiao TJ. Molecular Diagnosis & Therapy. 2010
Extreme phenotypes
Hsiao TJ. Molecular Diagnosis & Therapy. 2010

11. Energy Intake FTO (Fat Mass and Obesity Associated) Gene
High Risk allele (A vs. T) – 1 copy of the high risk allele = 30% more likely to be obese, 2 copies = 70%
Study of 131 children, 4-5 yo, those with a high risk allele ate more highly palatable food after a meal than those without even after controlling for BMI
Study of year olds, 34.7% of those with a high risk allele reported a loss of control over eating versus 18.2% without
In a subset of 190 participants who participated in a buffet test meal, total energy intake did not differ but fat intake was higher in those with a high risk allele
J Wardle. IJO. 2009; M Tanofsky-Kraff. Am J Clin Nutr. 2009

12. Energy Intake Dopamine (DRD2, DAT1/SLC6A3) Reward pathway
Study of 88 smokers with mean BMI of 27, those with a minor allele for DRD2 and a high score on a food reinforcement test consumed more calories
Those who were homozygous for the major allele for DAT1 and a high score consumed more calories
In non-smokers, only DRD2 findings were replicated
Extreme phenotypes
L Epstein. Behavioral Neuroscience. 2007; L Epstein. Am J Clin Nutr

13. Energy Intake Melanocortin-4 receptor (MC4R) gene
In 221 obese Chilean children one variant was found to be associated with satiety responsiveness and enjoyment of food scores.
In 1016 Hispanic children variation in MC4R was found to be related to energy intake reported on 24-hour dietary recalls
Extreme phenotypes
Valladares, M. Nutritional Neuroscience. 2010; Cole S. Am J Clin Nutr

14. Energy Expenditure Heritability for exercise participation: 62%
Heritability for resting metabolic rate: 40%
In the Negative Energy Balance Trial, twins were put on controlled diets and exercised 2X/day
Rankinen T. Med Sci Sports Exerc. 2010; Rankinen T. Obesity (Silver Spring). 2008; Bouchard C. Int J Obes. 1990

15. Discussion Does the genetic contribution to obesity matter?
Is it worth the cost?
How do we move forward with the information we have?