Obesity Genetics

Question 1

What methods can we use to quantify the heritability of a trait?

Answer 1

Twin studies
Adoption studies
Correlations with the genomic relationship matrix
Sibling studies

Question 2

How are twin studies used to quantify the heritability of a trait?

Answer 2

Look at the correlation between the trait in monozygotic twins
Look at the correlation between the trait in dizygotic twins
Compare the correlations. If the correlations are very different, the trait has a high genetic component

Question 3

What is a limitation of using twin studies to quantify the heritability of a trait?

Answer 3

Assumes that twins have grown up in exactly the same environment. If dizygotic twins are different sex, there is a good chance they will have been treated differently whilst growing up.

Question 4

What percentage of BMI is thought to be attributable to the genetic component?

Answer 4

30-40%

Question 5

How are sibling studies used to quantify the heritability of a trait?

Answer 5

Siblings share between 40-60% of their DNA. Look to see whether there is greater similarity in the trait between siblings that share 60% DNA rather than 40%.

Question 6

What is the effect of maternal obesity on offspring birthweight and why is this?

Answer 6

Maternal obesity associated with greater birthweight
Could be because maternal obesity leads to maternal type 2 diabetes, glucose passes through placenta, foetus produces insulin which is a growth factor

Question 7

What is the evidence suggesting that high BMI a causal factor of other diseases?

Answer 7

Using the mendelian randomisation approach, obesity has been shown to cause increased risk of psoriasis
Higher BMI may be a cause of depression, but a bi-directional relationship has not been ruled out

Question 8

What are the features of a rare mendelian form of a disease that is usually polygenic?

Answer 8

Young age of onset
Highly penetrant
Severe phenotype
Mendelian inheritance patterns

Question 9

Why are recessive conditions more likely to present in children of consanguineous marriages?

Answer 9

Both parents more likely to posses the a copy of the disease allele

Question 10

What is Prader-Willi syndrome?

Answer 10

Form of monogenic obesity also characterised by short stature, hypotonia, small hands and feet, and mild-moderate retardation

Question 11

What is the cause of Prader-Willi syndrome?

Answer 11

Defect of a gene on chromosome 15 that is normally maternally imprinted. The paternal copy becomes deleted or two maternal copies are inherited. No functioning alleles of the gene.

Question 12

How is appetite controlled by neurons within the brain?

Answer 12

Neurons in the arcuate nucleus receive hormone signals and pass signals onto effect neurons
NPY/AGRP neurons project orexigenic signals
POMC/CARt neurons project anorexigenic signals

Question 13

Mutations in which 4 genes are linked to obesity?

Answer 13

Leptin
LEPR (leptin receptor)
POMC/CART neuron
MC4R receptor

Question 14

What is the functional mechanism of leptin?

Answer 14

Secreted from adipose tissue
Binds to LEPR on NPY/AGRP neurons to suppress orexigenic signals
Binds to LEPR on POMC/CART neurons to stimulate anorexigenic signals

Question 15

What is the most common and severe type of monogenic obesity and how is it inherited?

Answer 15

Mutation in MC4R
Leads to loss of function or partial loss of function
Causes hyperphagia, hyperinsulinemia, increased lean mass
Codominant inheritance

Question 16

What is the function of MC4R?

Answer 16

MC4R is a receptor on downstream effector neurons

Receives anorexigenic signals from POMC/CART neurons

Question 17

What is The Leptin Story?

Answer 17

Knockout of the leptin gene in mice means they never stop eating
Could leptin be synthesised and injected into obese children to make them feel full and stop eating?
Maybe, but wouldn’t work for those with mutations in LEPR

Question 18

How can you test if a certain allele is associated with a disease?

Answer 18

Genotype cases and controls
Put results into a chi-squared test
Compare presence of allele in cases vs controls

Question 19

How can genetics influence the type of food we eat?

Answer 19

Certain variants in FGF21 increase affinity for
- snacking on sweet foods
- higher carbohydrate intake
- increased alcohol intake
Elevated fasting levels of FGF21 are associated with decreased affinity for sweet foods

Question 20

What is FGF21?

Answer 20

A hormone secreted by the liver after an oral sucrose load. Normalises blood glucose and reduces body weight

Question 21

What is codominant inheritance?

Answer 21

Both alleles fully expressed and produce proteins

The combinations of the alleles determines the phenotype

Question 22

What is mendelian randomisation?

Answer 22

When you have two associated factors, how do you know which way the causal arrow goes? Find a genotype that is associated with one of the factors.
Works because your genotype cannot be affected by confounding factors

Question 23

What are the BMI parameters for underweight, healthy, overweight, obese and morbidly obese?

Answer 23

<18.5 = underweight
18.5-25 = healthy
25-30 = overweight
30-40 = obese
>40 = morbidly obese