Polygenic Risk Scores

Question 1

Definition of tag SNPs

Answer 1

Representative SNP in a region of the genome with high linkage disequilibrium that represents a group of SNPs (haplotype)

Question 2

Definition of polygenic risk score

Answer 2

Predicts an individual’s risk of disease based on combination of their genotypes and effect size estimates from GWAS results

Question 3

Describe the relationship between genes and the environment

Answer 3

Environment can act on susceptibility genes

Environments are partially heritable

Question 4

Describe genes in complex diseases

Answer 4

Many genes are involved, each with a small effect

Genetic variations within genes contribute to a complex disease

Question 5

Describe the

• dominant genetic effect model
• additive genetic effect model

Answer 5

Dominant genetic effect
-if 1 different alleles present (AB, BB), has a dominant phenotypic effect

Additive genetic effect

• If 1 different allele present (AB, BB), has an additive phenotypic effect
• BB would have a stronger effect that AB

Question 6

What are the 4 benefits of GWAS

Answer 6

Detailed quality control possible
Unlimited findings
Clear statistical testing framework
Highly replicable

Question 7

Describe the method of GWAS

Answer 7

Find areas of linkage disequilbrium in a genome

Select tag SNPs so you can study common genetic variants

Genome wide SNP chips have DNA probes attached so you can test for the presence of certain variants

Findings plotted on a Manhattan plot

Any loci with high statistical significance mapped onto chromosome

Question 8

What are the 3 main findings in GWAS studies

Answer 8

Common variants with low effects often found in common disease

Low frequency variants with intermediate effect are fairly rare

Few examples of high effect common variants in common diseases

Question 9

What are the 5 key properties of a GWAS

Answer 9

Looks for causal variants associated with phenotypes in the genome

Trait to be studied must be heritable

Tests are normally performed 1 SNP at a time on 1 outcome

As the chance that any SNP has a causal effect on the phenotype is low, p =5x10^-8

Disease risk alleles are passed on with other alleles
Even if the causal variant is not genotyped, other SNPs nearby may be correlated with it

Question 10

What are the 2 potential uses of GWAS in the future

Answer 10

Predict the disease and traits that are likely to be present

Aggregating predictions across samples can be used to build up an evidence base

Question 11

How would you alter GWAS so it could be used in phenotype predictions for polygenic traits

Answer 11

GWAS aimed to discover susceptibility loci
To predict phenotypes of polygenic traits
-include more variants by varying the p threshold

Question 12

What is a polygenic risk score

Answer 12

Predicts an individuals risk of disease based on combination of their genotypes and effect size estimates from GWAS resultsa

Question 13

Why is a polygenic risk score useful

-4 reasons

Answer 13

Assess shared genetic aetiology among phenotypes
Biomarker for disease
Infer if a biological factor is causally associated with a disorder
Screen subjects for clinical trials

Question 14

How would you calculate a polygenic risk score

Answer 14

Sum of risk alleles from genome wide SNPs, weighed by their GWAS derived effect size estimates

Only SNPs exceeding the p value threshold contribute to the score

PRS is calculated for several p values in individuals of a target data set

Regression performed to test for association between PRS and trait in target sample

Question 15

What are the potential uses of polygenic risk scores

Answer 15

Individuals could be placed on a spectrum of genetic burden to a trait

Could be used clinically

Question 16

What are the 2 challenges associated with polygenic risk scores

Answer 16

Most PRS studies have been performed in Europeans
-need more data on other ancestral backgrounds

Need to build up evidence base so it can have

• increased predictive ability
• used clinically