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
It is difficult to pursue large GWAS (>5K cases).
How can this be overcome?
Easier to combine smaller studies
- Pre-experiment – Group of groups or
- Post-experiment - Meta-analysis
Meta-analysis is the statistical combination of results from multiple studies
How is cardiac conductivity measured?
ElectroCardioGram
What does an ECG reflect?
ECG : reflects different parameters
> variation measured in ms
What are the different ECG intervals as part of the ECG trace ?
- PR interval : atrial depolarization
- QRS interval : ventricular depolarisation
- QT interval : ventricular de and repolarisation
- RR interval : 1 cycle (heart rhythm)
These are used for GWAS
How has a WGS GWAS for QRS been facilitated?
- 405k ECGs in 81K Icelanders
- WGS in 15k Icelanders for imputation
- 32.5 million variants tested
- 123 QRS complex parameters
- Weighted Bonferroni
- 190 loci associated with QRS
Norland et al (2019) Nature Comms 10: Article 4803
What is QT prolongation associated with?
- Sudden cardiac death
- (drug-induced) cardiac arrhythmias
Drug induced arrhythmias are rare however why are they potentially life threatening?
Because of association with SCD – potentially life-threatening
And despite known risk factors – not highly predictable…
What is Amiodarone ?
A potent anti-arrhythmic agent used to treat various types of tachyarrhythmias
Associated with a high incidence of side-effects, such as QT prolongation that may lead to fatal arrhythmias
GWAS studies have shown consistent association between QT interval and NOS1AP (see earlier)
One study found common variants in the NOS1AP gene play a role in the pathogenesis of amiodarone-induced QT prolongation and consequent arrhythmias
What are features of the UK biobanks?
Recruited 500,000 people aged between 40-69 years in 2006-2010 from across the UK
Genome-wide genotyping for all, exome sequencing in 200,000, WGS to follow
Wide range of phenotypic measures
What are UK Biobank Phenotypes?
Questionnaire-based
- Sociodemographic factors
- Smoking and Alcohol
- Family history and Early-life exposures
- General Health and Disability
- Environmental Factors
- Dietary Habits
- Psychological and Cognitive State
Physical Measurements
- Blood pressure and pulse rate
- Weight/Height/Waist and Hip Circumference
- Body fat (Bio-impedance)
- Hand grip strength
- Spirometry
- Bone densitometry
Samples
- Blood
- Urine
Biomarkers
- 34 currently
- Of interest - Cholesterol, LDL, HDL-cholesterol, Triglyceride, ApoA, ApoB, CRP, Lp(A)
What information does the UK Biobank include concerning CAD?
4,831 cases
115,455 controls
820k markers in Axiom Array (ThermoFisher)
Imputed ~9 million sequence variants
Several genes with associated SNPS, for which no known prior evidence of their involvement in CAD
Issue with GWAS is trying to understand role of such unknown genes
What is a recent initiative by the UK biobank?
Pharma proteomics projects
