GWAS of CVD 1 Sudden Cardiac Flashcards

1
Q

What is sudden cardiac death?

A

Death from definite or probable cardiac causes within 1 hour of onset of symptoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the incidence of sudden cardiac death?

A
  • > 50% of all Coronary Heart Disease deaths

- Up to 20% of all deaths

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Under 35 years of age SCD is not so common but typically is caused by what?

A
  1. Channelopathies (ion channel disorders): 1/2000
  2. Cardiomyopathies
    - Hypertrophic Obstructive Cardiomyopathy:1/500
    - Arrhythmogenic Right Ventricular Dysplasia: 1/1000
    - Dilated Cardiomyopathy: 1/2500
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are characteristics of Channelopathies?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the second leading cause of death in the UK?

A

Coronary Heart Disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Over 35 years of age SCD is typically caused by what?

A

Coronary Heart Disease: 1/33

1/8 men and 1/13 women will die from this

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is a complex disease?

A

This is a disease in which both genetic and environmental factors play a part

Complex diseases are much more common than Mendelian diseases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is genetic association?

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What do case-control studies involve?

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What can be used to facilitate statistical significance of case control association?

A

Chi-squared test to compare cases and controls

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why is association useful?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are Quantitative Traits?

What are the advantages and disadvantages of measuring Quantitative Traits?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What steps are involved in a GWAS?

A
  1. Recruit large numbers
  2. Genotype many SNPs
  3. Plot significance of association against genome location
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is typically used for genotyping?

A

SNP Microarrays

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What does GWAS statistics involve?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

It is difficult to pursue large GWAS (>5K cases).

How can this be overcome?

A

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

17
Q

How is cardiac conductivity measured?

A

ElectroCardioGram

18
Q

What does an ECG reflect?

A

ECG : reflects different parameters

> variation measured in ms

19
Q

What are the different ECG intervals as part of the ECG trace ?

A
  • 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

20
Q

How has a WGS GWAS for QRS been facilitated?

A
  • 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
21
Q

What is QT prolongation associated with?

A
  • Sudden cardiac death

- (drug-induced) cardiac arrhythmias

22
Q

Drug induced arrhythmias are rare however why are they potentially life threatening?

A

Because of association with SCD – potentially life-threatening

And despite known risk factors – not highly predictable…

23
Q

What is Amiodarone ?

A

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

24
Q

What are features of the UK biobanks?

A

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

25
Q

What are UK Biobank Phenotypes?

A

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)
26
Q

What information does the UK Biobank include concerning CAD?

A

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

27
Q

What is a recent initiative by the UK biobank?

A

Pharma proteomics projects