Complex Disease Flashcards
Definitions of complex disease
Many loci across the genome with weak effects
Can be affected by environmental factors
Definition of penetrance
Chances of developing disease
What are the main 4 properties of complex diseases
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
What are the 2 ways you would assess the genetic contribution to a disorder
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
What are the types of genes associated with complex disease
small no of high risk genes
larger no of lower risk genes
What are the main differences between Mendelian and Complex diseases
- no of genes involved
- predictive value
- inheritance pattern
- rarity
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
Describe the distribution of quantitative vs discrete complex traits
- 1 locus
- many loci
1 locus
-3 bars, 1 locus explains all variability
Many loci
-standard distribution, 1 locus explains small % of variability
Describe the distribution of liability in
- the general population
- families
General population
-High threshold value of liability with a small percentage affected
Families
-Mean shifted upwards so a greater percentage is affected
How would you use genetic association studies and GWAS to identify polygenic disorders
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
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
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
What type of risk estimates would you calculate for and why
- mendelian disease
- polygenic disease
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
How would you analyse the results from GWAS case controls
What is the p value
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
What is a polygenic risk score
why is it not used clinically
Use combined info across SNPs to estimate disease risk
- all heritable not explained
- environmental risk not fully understood
How is your genetic risk affected by environment
Who can this info be used for
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
