The Genetics of Common Disease

Question 1

What does genetic variation cause?

Answer 1

It leads to phenotypic differences

Question 2

What are mendelian diseases?

Answer 2

Diseases caused by a mutation in one gene

Question 3

Give an example of a mendelian disease

Answer 3

Cystic fibrosis - a three base deletion removing the phenylalanine codon

Question 4

What is the genetic cause of most common traits/diseases?

Answer 4

Most are multi-factorial so many genes may affect the disease/trait.

Question 5

Examples of multifactorial diseases

Answer 5

Type 2 diabetes
Hypertension
Alzheimers disease

Question 6

What is heritability?

Answer 6

It is a measure of how well differences in people’s genes account for differences in their traits.

Question 7

How is heritability calculated?

Answer 7

Using twin studies

Question 8

If heritability is close to one what does this indicate?

Answer 8

It indicates that almost all of the variability in a trait comes from genetic differences, with very little contribution from environmental factors.

Question 9

If a trait is has a higher concordance in monozygotic twins, what does this mean?

Answer 9

It means the more of a trait is determined by a genetic contribution rather than environmental like in dizygotic twins

Question 10

How is heritability of ECG indices estimated?

Answer 10

By looking at the difference in the correlation of monozygotic (MZ) and dizygotic (DZ) twin pairs.

Question 11

What does a high heritability score mean?

Answer 11

There is a stronger resemblance

Question 12

What is a SNP?

Answer 12

A single change in a base pair. The most common variation in the human genome .

Question 13

What are SNPs used to identify and how?

Answer 13

Using GWAS, they are used to identify genes involved in complex diseases.

Question 14

What is the purpose of a typical GWAS?

Answer 14

• A typical GWAS collects data to find out the common variants in a number of individuals, bot with and without a common trait (e.g. a disease), across the genome, using genome wide SNP arrays.

Question 15

Simply describe how a SNP microarray works

Answer 15

• Amplify and fragment the target gene
• Hybridise by capturing and labelling when it binds to the array
• Labelled probes bind to sample, differentiating between the two alleles
• Make it bright enough then measure intensity of the array to confirm how many SNPs are present

Question 16

Why is SNP-SNP association or linkage disequilibrium important?

Answer 16

It is fundamental to our ability to sample the whole genome with relatively few SNPs

Question 17

Define linkage disequilibrium (LD)

Answer 17

The difference between the observed frequency of the particular combination of alleles at two loci and the frequency expected for random association

Question 18

What decreases between two SNPs if there is distance?

Answer 18

LD decreases as it is more likely to have a recombination event between them.

Question 19

Where does the LD vary?

Answer 19

The extent the LD varies depends on the region of the genome

Question 20

When can strong LDs be beneficial?

Answer 20

It is beneficial as there is fewer SNPs needed to capture variation in a region so cheaper and quicker to analyse

Question 21

What is the causal variant?

Answer 21

The variant responsible for the association signal at a locus

Question 22

How is the causal variant identified?

Answer 22

Often the causal variant is not included on the SNP chips so further work is required to narrow down the region of association and identify the causal variant.

Question 23

When are variants found at a higher frequency?

Answer 23

They are found at a higher frequency in disease/trait cases than in controls.

Question 24

Why is statistical analysis carried out in GWAS?

Answer 24

To indicate how likely a variant is to be associated with a trait

Question 25

How are GWAS results displayed?

Answer 25

In a manhattan plot, plotted against the position in the genome.

Question 26

What is the P value threshold for most GWAS to correct for multiple testing?

Answer 26

5 x 10^-8

Question 27

What is the bonferroni correction?

Answer 27

If the number of tests (SNPs genotyped) is n, we set the threshold to be 0.05/n. This will identify a SNP that is significantly associated with disease, there are three possibilies:

• Causal relationship between SNP and disease
• Marker is in linkage disequilibrium with a causal locus
• False positive

Question 28

Short term goal of GWAS

Answer 28

To identify genetic regions that explain differences in phenotype among individuals in a study population.

Question 29

Why are further studies carried out after GWAS?

Answer 29

To determine the causal variants
To understand the mechanism of action and disease etiology in individuals
To characterise relevance and/or impact in more general population.

Question 30

Long term goal of GWAS

Answer 30

To inform process of identifying and delivering better prevention and treatment strategies