Heritability of complex disease

Question 1

What can we conclude from the genetics of more complex diseases compared with single gene disorders?

Answer 1

Predisposition to a condition is determined by the complex interplay of the genotype at many different gene, and the effects of the environment, all possibly interacting with eachother in complex manners.

Question 2

‘Is the disease caused by something in the genes, or something in the environment?’ WHy does this statement not make sense?

Answer 2

Environmental - Speaking english
Genetics - The ability to speak english

Question 3

What is the ideal question to ask about a disease/trait

Answer 3

How heritable is it…

Question 4

What does heriatiblity measure?

Answer 4

Measures the extent to which variation in a trait within a particular population is due to variation in genetics.

Question 5

How do we first go about measuring heritability?

Answer 5

Need to break down variation of the trait/disease/phenotype into genetic and environmental components.

Question 6

Whats the most common model to explain vairance?

Answer 6

ACE model
A - Additive Genetic variation
C - Common environment
E - Non-common/non-shared environment

Question 7

What is deviance

Answer 7

Each individual differs from thr population average by some amount#Deviance is related to variance

Question 8

In individuals, what is their deviance a result of?

Answer 8

Genetic deviance
Environmental deviance

Question 9

What is genetic deviance

Answer 9

How they genetically differ from the average

Question 10

What is environmental deviance

Answer 10

How much individuals environmental causes differ from the average.

Question 11

How do we look at genetic influence on phenotypes in humans?

Answer 11

Monozygotic twin studies

Question 12

What is broad sense heritability?

Answer 12

refers to all genetic effects – how your DNA contributes to phenotype

Question 13

What is narrowsense heritability?

Answer 13

refers to just the additive effects.

Question 14

What is a problem with Monozygous twin studies?

Answer 14

Assumes that the environmental difference between monozygoutic twins is representative of the environmental difference in the population. Which isnt true.
Twins tend to share more of their environment with each other than two random membraer of the population.

Question 15

What is the shared/common environment?

Answer 15

This extra environment twins have in common. Represented by C in ACE model.

Question 16

What is the non-shared/non-common environment?

Answer 16

Way in which the environment of twins differ. Represented by E.

Question 17

How do we disentangle the effects of the shared and non-shared environment?

What can we assume?

Answer 17

Use dizygotic or non-identical twins.

We assume that dizygotic twins share the same amount of environment with each other as monozygotic twims. But they only share the same half as much of their genetics with eachother as monozygotic twins.

Question 18

What can we conclude from dizygotic twins about genetics and environment when comparing to monozygotic twins?

Answer 18

IF dizygotic twins differ from eachother more than monozygotic twins do, it must be down to this different in genetics.

If dizygotic twins share half their genetics (on average), instead of all their genetics, we might conclude that the total amount of genetic contribution is twince the difference in the similarity of mono- and di- zygotic twins.

Question 19

Explain dominance relationships

Answer 19

WHere the heterozygote has the same phenotype as one or other of the homozygotes.

Question 20

Explain epistasis

Answer 20

Where the effects at one locus depend on the effects at another locus.

Question 21

What are dominance relationships and epistasis cases of?

Answer 21

Where genetics are non-linear, and if either are present, then the twin method will overestimate the additive genetic component.

Question 22

How can you detect if the genetics are non-linear?

Answer 22

To look at value of c

If 2rDZ - rMZ < 0 = there must be dominance or epistasis effects at work (although C>0 does not necessarily mean there is not).

Question 23

What do twin studies measure?
How is the estimate inflated?

Answer 23

Measures broad sense heritability (H2), under the assumption that all genetic effects are additive. (H2=h2)
Estimate will be inflated if there are Dominance or epistatic effects.

Question 24

If 2𝑟_𝐷𝑍−𝑟_𝑀𝑍<0, then 𝐶<0, , what can we assume? What do we then use?

Answer 24

If 2𝑟_𝐷𝑍−𝑟_𝑀𝑍<0, then 𝐶<0, and we therefore assume that there must be dominance effects at work, so we use an ADE model
Can’t estimate C and D at the same time, only one or the other.

Question 25

Is it true that 𝐶_𝑀𝑍=𝐶_𝐷𝑍?

Answer 25

In utero environment
Are MZ and DZ twins treated the same?

Question 26

Whats a second assumption about twin methods?

Answer 26

Is that monozygotic and dizygotic twins share the same amount of common environment

Question 27

Why might MZ and DZ twins not share same amount of common environment?

Answer 27

Parents might trear mono-zygotic twins more alike than DZ twins. MZ twins also have a different in-utero environment to DZ twins.

Question 28

What are the alternatives to twin studies?

Answer 28

Add

Question 29

Example of a study estimating geneitc heritability

Answer 29

• 15 million swt of twins - 17,804 traits.
• Looked at : Height, blood pressure, metabolic status, depression and personality disorders.
• They calculated A, C and E using fixed effect linear models

Question 30

WHat are fixed effect linear models?

Answer 30

In statistics, a fixed effects model is a statistical model in which the model parameters are fixed or non-random quantities.

Fixed effects is a statistical regression model in which the intercept of the regression model is allowed to vary freely across individuals or groups.

Question 31

What did the study of estimating genetic heritability find?

Answer 31

Found whule some traits have low heritability and some with high heritability - there was a strong average at around 0.5

Basically, on average additivt genetics effects accounts for half of the variation in traits, and many traits were close to this average.

Question 32

What also did they find about twins?

Answer 32

Found 69% of cases the data was compatibility with a common environment effecr of 0.
Twins shared no more of their relevant environment than any two randon people.
Although did find stronger common environments where expected - like more psychological traits.

Question 33

Describe DISCOTWIN T2D study

Answer 33

35,000 twins from across Europe.
Fpund heritability of type 2 diabetes (T2D) in adults over 45 was 72% - pretty high!

Question 34

Washington state twin registry T2D study - what was concluded

Answer 34

Small number of students
Found heritability of 52% in adults over 45,
A lower heritability of 22% in people under that.

From the same study using twins from the same state, find different populations (younger and older) have different heritabilities.

Could be due to chance and small numbers?

Question 35

Botnia T2D study

Answer 35

Small study from finland.
Found heratibility of 69% in adults aged 35-60, but if looked at participants under 75% they found heritability of 31%

Question 36

What are possible explanation of the differences in these 3 studies?

Answer 36

Genetics of US and european populations are different
Obesity and food environment have a strong effect on diabetes and that the food environment is different between Europe and Us.
Obesogenic environment more common is US.

Environment conditiond lead to diabetes are less common in europe, therefore chance of getting diabetes is more down to you genes alone.

Question 37

WHat is the main message
and how do we estimate this?

Answer 37

We cannot assess ‘how genetic’ a disease is, only how much variation n it is due to genetic variation, and is specfic to a particular time and place.

Using the ACE model

Question 38

What does the ACE model assume?

Answer 38

that Mz and DZ twins share the same amount of environment, and all genetic variation is additive ( i.e there is no dominance or epistasis).

Question 39

How could a certain amount of heritability be explained by genes and variants?

Genetic architecture.

Answer 39

Genes and/or variants could each have a small effect, or a small number of genes/variants having large effect: what we called the genetic architecture of a condition.

Question 40

What needs to be thought about when looing for genes invovled with complex disease

Answer 40

Two different measures of how important they are, or what fraction of the heritability is down to that variant - how common is an allele and how big is the effect of having that allele.

Question 41

Different measures of how big the effect of an allele is

Answer 41

Genotype Relative RIsk
The Odds Ratio

Question 42

Genotype Relative RIsk

Answer 42

What is the probability of having the disease if you have the risk genome type relative to the probability uif you have the pretective genotype.

.. so if you are twice as likely to get the disease if you have A rather than T, the GRR is 2.

Question 43

The Odds Ratio

Answer 43

The odds of getting the disease if you have the risk genotype relative to the odds if you don’t

Here the odds is the number of people with the disease divided by the number of people without it.

Question 44

What are the Genotype relative risk and Odds ratio talking about?
What else needs to be considered?

Answer 44

Disease vs non-disease

Continuous traits like height, BMI, blood-pressure - in these cases the effect size is measured by Beta.

Question 45

What are the Genotype relative risk and Odds ratio talking about?
What else needs to be considered?

Answer 45

Disease vs non-disease

Continuous traits like height, BMI, blood-pressure - in these cases the effect size is measured by Beta.

Question 46

What is Beta?
Give an example

Answer 46

The amount of trait changes for each additional allele.

Example - for height, a Beta of 1 might mean height increases by 1cm for each allele

Question 47

What does an allele that has a big effect have?

Answer 47

An allele that has a big effect has a big genotype relative risk or big odds ration - but that doesnt mean that it explains a lot of the heritability.

Question 48

How can different possibilities for disease allele be visualised?

Answer 48

On a plot with Allele Frequency on one axis and effect size on the other.

Question 49

When does a disease behave as a mendelian disorder?

Answer 49

If effect size is big, such that people with the risk allele almost always have the disease and those without it don’t

Question 50

What is ideal to identify?
Give 3 examples

Answer 50

Identify genes that are both common and have a large effect. If such genes exist, they have been identified.

DQB1 in type 1 diabetes
ApoE e3 allele in Alzheimers
Mutation in CFH gene

Question 51

Describe DQB1 in type 1 diabetes

Answer 51

A change of Asp57 to any toehr amino acid has a very large effect.

Homozygous Odds ratio is 18, but 3% of the population is homozygous, only 0.3% of population get T1D.

Genetics is not predestination.

This is the largest effect size found of any allele for a complex disease, but only 10% of those who are homozygous for it will get the disease.

Question 52

Describe ApoE e3 in Alzheimers

Answer 52

Has an heterozygous Odds ratio of 2.5
Has an homozygous Odds ration of 13.
Allele frequency of 16%

Question 53

CFH gene, Wet Mucular degeneration

Answer 53

CFH gene offers protection from Wet macular degeneration.
Adds ratio of 5 - those with the risk allele have odds 5 times more than those without.
These effects were discovered in the pre-GWAS era.

Question 54

WHat are the group of alleles addressed by Genome-wide association studies.

Answer 54

Disease alleles are common, but only have a small effect.