GWAS of CVD 1 Sudden Cardiac Flashcards
What is sudden cardiac death?
Death from definite or probable cardiac causes within 1 hour of onset of symptoms
What is the incidence of sudden cardiac death?
- > 50% of all Coronary Heart Disease deaths
- Up to 20% of all deaths
Under 35 years of age SCD is not so common but typically is caused by what?
- Channelopathies (ion channel disorders): 1/2000
- Cardiomyopathies
- Hypertrophic Obstructive Cardiomyopathy:1/500
- Arrhythmogenic Right Ventricular Dysplasia: 1/1000
- Dilated Cardiomyopathy: 1/2500
What are characteristics of Channelopathies?
Electrical current in heart is generated by channels that move ions (Na+, K+, Ca2+) in and out of cells
Mutations in ion channel genes can cause electrical instability and increase chance of arrhythmia:
- Long QT syndrome
- Brugada syndrome
- Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Occurs in a ‘structurally normal heart’ but arrhythmia usually detectable on ECG
Typically monogenic disorders, small fraction of SCD
What is the second leading cause of death in the UK?
Coronary Heart Disease
Over 35 years of age SCD is typically caused by what?
Coronary Heart Disease: 1/33
1/8 men and 1/13 women will die from this
What is a complex disease?
This is a disease in which both genetic and environmental factors play a part
Complex diseases are much more common than Mendelian diseases
What is genetic association?
The presence of an allele at a higher frequency in unrelated subjects with a particular disease/trait (cases) compared to identical subjects who do not have the disease/trait (controls)
What do case-control studies involve?
Cases are subjects with the trait of interest, e.g. MI, stroke, hypertension
Definition of the trait must be applied in a rigorous and consistent way
Controls are as well-matched as possible
Age, sex, ethnicity, location, etc.
What can be used to facilitate statistical significance of case control association?
Chi-squared test to compare cases and controls
Why is association useful?
Association occurs over relatively short distances in the genome, typically <100kb
Association of a marker with disease should mean you are very close to the causal variant
SNPs are markers of choice in GWAS
What are Quantitative Traits?
What are the advantages and disadvantages of measuring Quantitative Traits?
Traits that can be measured, e.g. pulse rate
Also called continuous traits
Advantages - accurate and reproducible, statistically powerful
Disadvantages – expensive to measure in large numbers
What steps are involved in a GWAS?
- Recruit large numbers
- Genotype many SNPs
- Plot significance of association against genome location
What is typically used for genotyping?
SNP Microarrays
What does GWAS statistics involve?
Test each SNP for association with disease
Use chi-squared test for SNP/disease status
Correct p-value to reflect number of tests (Bonferroni correction)
p<0.05 becomes p<5x10-8