Genetics of common disease

Question 1

Familial clustering

Answer 1

Phenotypes and disorders, that occur more likely in families than unrelated individuals

Question 2

Genes and the environment

Answer 2

They don’t occur with single gene/mendelian disorders - they occur with a mixture of genes and environment

Question 3

Main point

Answer 3

A person will have a complex disorder/trait if they have the right combination of genetic differences and environmental exposures.

Question 4

Twin studies

Answer 4

Monozygotic twins - Share 100% of germline genetic variation

Dizygotic twins - Share 50% of germline genetic variation

Question 5

Estimating heritability

Answer 5

Heritability (h2) is the proportion of variation in a trait explained by inherited genetic variants

Question 6

Correlation

Answer 6

1 indicates a strong positive relationship
-1 indicates a strong negative relationship
0 indicates no relationship at all

Question 7

Electrocardiogram

Answer 7

• Cardiac conductivity : ElectroCardioGram

* ECG Intervals measured in ms

Question 8

Heritability of cardiac electrical function

Answer 8

h2 scored between 0 and 1

High heritability = strong resemblance

Question 9

What do you do after heritability?

Answer 9

GWAS
Once you have determined that a phenotype/disease is influenced by genetic variation i.e. the trait heritability is >0.4 the next step is to identify what that genetic variation is.

Question 10

Heritability - genetic susceptibility

Answer 10

13,000 adult same-sex twins from the UK, recruited since the 1990s.
>3000 traits have been measured in these twins.
Many published heritability studies.

Question 11

Genetic association study

Answer 11

What are the genetic variants that are associated with variation in human disease risk, or a human trait/phenotype?
Categorical: disease yes/no
Continuous: BMI, heart rate, height

Question 12

Common variation

Answer 12

Our genomes vary from person to person.
Often, a difference will be in just one base pair.
These variations are called:
SINGLE-NUCLEOTIDE POLYMOPRHISMS (SNPs)*
They are the most common variation in human genome.

Question 13

Genotyping loads of SNPs

Answer 13

Commercial probe-based SNP array platforms (e.g. Illumina) can now genotype, with >99% accuracy, about one million SNPs in an individual in one assay.

Question 14

Linkage disequilibrium and SNP array design

Answer 14

Rather than directly measuring genotypes at all genetic polymorphisms, we rely on association between the polymorphisms we do assay and those which we do not assay.
SNP-SNP association, or linkage disequilibrium (LD), is fundamental to our ability to sample the whole genome with relatively few SNPs.

Question 15

Linkage disequilibrium

Answer 15

Linkage Disequilibrium is defined as the difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association.

Question 16

LD and SNPs

Answer 16

In general, LD between two SNPs decreases with physical distance as more likely to have a recombination event between them.
Extent of LD varies greatly depending on region of genome i.e. recombination hot spots.
If LD strong, need fewer SNPs to capture variation in a region – cheaper and easier/quicker to analyse.
The first SNP chips had at least 317,000 SNPs distributed across the genome.
Newest: >1 million.

Question 17

GWAS

Answer 17

Variants associated with the disease/trait (or within the same haplotype as a variant associated with a disease), will be found at a higher frequency in cases than in controls.
Statistical analysis is carried out to indicate how likely a variant is to be associated with a trait.

Question 18

Goal of GWAS

Answer 18

• Identify genetic regions that explain differences in phenotype among individuals in a study population
i.e. to better understand the biology of the disease/phenotype
• To identify genetic variants that can be measured to determine whether an individual is at higher risk of disease
• To identify potential drug targets to treat the disease