Complex Disease

Question 1

Definitions of complex disease

Answer 1

Many loci across the genome with weak effects

Can be affected by environmental factors

Question 2

Definition of penetrance

Answer 2

Chances of developing disease

Question 3

What are the main 4 properties of complex diseases

Answer 3

Raised risk in families
-but increase in risk may be slightly different with population risk

No clear mode of inheritance

Multiple genes => disease risk

Environmental effects may contribute

Question 4

What are the 2 ways you would assess the genetic contribution to a disorder

Answer 4

Twin studies

• MZ. DZ concordance compared
• Heritability estimated (relative measure to surrounding environmental effects)
• Also can interact with environment
• If concordance higher in MZ => genetic component present

Family studies
-assess if there is an increased risk in families than population risk

Question 5

What are the types of genes associated with complex disease

Answer 5

small no of high risk genes

larger no of lower risk genes

Question 6

What are the main differences between Mendelian and Complex diseases

• no of genes involved
• predictive value
• inheritance pattern
• rarity

Answer 6

No of genes involved
M, 1 gene involved
C, multiple

Predictive value
M, knowledge of genotype highly predictive
C, knowledge of single factor is not predicitve

Inheritance pattern
M, dominant, recessive
C, no clear inheritance pattern but can run in families

Rarity
M, rare
C, more common

Question 7

Describe the distribution of quantitative vs discrete complex traits

• 1 locus
• many loci

Answer 7

1 locus
-3 bars, 1 locus explains all variability

Many loci
-standard distribution, 1 locus explains small % of variability

Question 8

Describe the distribution of liability in

• the general population
• families

Answer 8

General population
-High threshold value of liability with a small percentage affected

Families
-Mean shifted upwards so a greater percentage is affected

Question 9

How would you use genetic association studies and GWAS to identify polygenic disorders

Answer 9

Tests whether presence of a specific genetic variant increases disease risk

GWAS genotype up to 1mn SNPs across the genome
-used to identify genes for polygenic disorders

Question 10

How would you test for association in a case control

• What do you need to consider in the cases and the controls
• What stats test would you do
• What would be your conclusion if there is a significant risk

Answer 10

Cases

• affected with disease
• clear clinical criteria for inclusion
• geographic and ethnic background info

Controls

• random population samples/screened healthy individuals
• geographic and ethnic background info

Chi squared
Significant result => SNP influences disease risk

Question 11

What type of risk estimates would you calculate for and why

• mendelian disease
• polygenic disease

Answer 11

Mendelian

• Absolute risk = no people with genotype/total no in group
• calculate penetrance (chances of developing disease)

Polygenic disease

• Relative risk/Odds ratio = genotypes in cases/genotypes in controls
• each variant only has a small effect on risk and must be combined with other contributing genes

Question 12

How would you analyse the results from GWAS case controls

What is the p value

Answer 12

Logistic regression used instead of x2 as covariates can account for confounders (population structure)

Plot the results on a Manhattan plot (significance of association against position on chromosome)

p = 5x10-8

Question 13

What is a polygenic risk score

why is it not used clinically

Answer 13

Use combined info across SNPs to estimate disease risk

• all heritable not explained
• environmental risk not fully understood

Question 14

How is your genetic risk affected by environment

Who can this info be used for

Answer 14

Low genetic risk
-poor environment will increase risk

High genetic risk
-healthy environment will decrease risk

Can’t calculate individual risk but tells you about the population risk