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Genomics > Genetics of Common Disease > Flashcards

Genetics of Common Disease Flashcards

1
Q

What is the effect of genetic variation?

A

Leads to phenotypic differences

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2
Q

What is the occurrence of genetic variants in cases compared to controls?

A

Genetic variants, and those that are tightly linked to their region of the chromosome, are present at a higher frequency in cases compared to controls

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3
Q

Which loci are genetic variants seen?

A

Genetic variants travel with variants close together (linked loci)

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4
Q

In which cases do we see the phenotypic effect of genetic variation?

A

The idea of genetic variation influencing phenotypes applies to rare diseases and common diseases such as heart disease, high BP as well as hair color and IQ.

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5
Q

As an example explain the frequency of variants in CHD patients (coronary Heart disease)

A

Coronary heart disease patients will show a region of the genome higher in frequency in cases compared to the controls; suggesting that region contains a gene / several genes that influences the phenotype / trait

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6
Q

How are common variants identified?

A

Common variants and disease can be identified via linkage analysis (same as rare variants)

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7
Q

What is the major cause of Mendelian disease?

A

Most cases are due to one gene and often the majority are due to one particular mutation

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8
Q

Give an example of a mendelian disease due to a mutation?

A

CysticFΔ508 is a three-base deletion, removing a phenylalanine codon

Inheritance pattern is clear: recessive loss of function, autosomal dominant, X-linked
Minimal influence from environment

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9
Q

How does CF variants differ from other traits?

A

Doesn’t apply to most common disease, or most phenotypic rates e.g. height, BP, HR etc.

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10
Q

What are CDCVs?

A

Common Disease Common Variants

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11
Q

What does the CDCV hypothesis state?

A

’ common disorders are likely influenced by genetic variation that is also common in the population’

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12
Q

What does CDCV state about effect size of variants?

A

Effect size (or penetrance) for any one variant must be small relative to that found for rare disorders

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13
Q

How does inheritance relate to CDCV?

A

If common alleles have small genetic effects, but common disorders show heritability (inheritance in families) then multiple common alleles must influence disease susceptibility

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14
Q

How many genes influence a trait?

A

Multiple genes can play a role in determining a phenotype and/or disease
Common diseases are often multifactorial

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15
Q

What are the main factors influencing complex disease?

A

Multiple genes may affect the disease
There is a strong influence of the environment
Therefore, the effect of every single gene may be negligible

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16
Q

Give examples of complex disease influenced by both genotype and environment

A
  • Type 2 diabetes
  • Hypertension
  • Alzheimer disease
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17
Q

What is heritability?

A

A measure of how well differences in people’s genes account for differences in their traits

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18
Q

How can we tell if variability is due to inheritance or the environment?

A

A heritability close to 1 indicates that almost all of the variability in a trait comes from genetic differences with very little contribution from environmental factors

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19
Q

How do we calculate heritability?

A

We can calculate heritability using twin studies

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20
Q

What are monozygotic twins/

A

Monozygotic twins: genetically identical

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21
Q

What are dizygotic twins?

A

Dizygotic twins: share 50% of genes with each other (equivalent to siblings)

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22
Q

Why is twin studies a good way of analysing gene variants?

A

Can rule out environment as a factor, any difference seen is due to trait

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23
Q

How can we identify a trait is due to genes?

A

The more a trait is determined by a genetic contribution the greater the difference between monozygotic and dizygotic twins

Any concordance of >40% is significance to look at and carry out GWAS

24
Q

What is an ECG?

A

ElectroCardioGram shows us Cardiac conductivity

Electrical conduction system of the heart

25
Q

What units are ECG intervals measured in?

A

ECG intervals are measured in ms

26
Q

What does an ECG interval show?

A

Each interval shows the typical pattern of the heart and reflects an activity occurring through the heart

P wave - atrial conduction initiation
QRS - ventricular conduction
T interval - resetting back to beginning
R - R interval - heart rate

27
Q

How are we able to identify the heritability of ECG indices?

A

Estimated by looking at the difference in the correlation of monozygotic (MZ) and dizygotic (DZ) twin pairs

28
Q

What does a high heritability tell us?

A

High heritability implies a strong resemblance

A score between 0-1 (closer to 1 = more heritable)

29
Q

Outline the benefits of NGS

A

faster, cheaper technologies for sequencing DNA and assessing variation in genomes

30
Q

What are SNPs?

A

SINGLE-NUCLEOTIDE POLYMORPHISMS - difference in base pair

31
Q

What is the significance of SNPs?

A

SNPs could now be used to identify genes involved in complex diseases using the Genome WIde Association Study (GWAS)

32
Q

What does a typical GWAS study involve?

A

A typical GWAS study collects data to find out the common variants in a number of individuals, both with and without a common trait (e.g. a disease) across the genome, using genome wide SNP arrays

33
Q

How are SNPs microarrayed?

A
  1. Prepare DNA and fragment it
  2. Tag with fluorescent probe
  3. Mix with oligonucleotides slides that match with region
    of genome around each variant being tested
  4. DNA sample will bind to matching oligonucleotide and
    fluoresce in different colour depending on base
    (C,G,T,A)
  5. As we know where SNP is located on the chip we can
    calculate the genotype
34
Q

What is the problem when SNP array results aren’t clear

A

Doesn’t always work perfectly computer diagrams unclear - when carrying out study can get false results where individuals aren’t allocated the correct phenotype

35
Q

How is the computer diagram of SNP microarray results converted?

A

This diagram is then converted in a computer into code

36
Q

What is the purpose of converting SNP results into code?

A

Calculates everyone’s genotype at different SNPs
Converts into binary code
Most common variant listed first

37
Q

How many SNPs are contained in an SNP chip?

A

A “typical” SNP chip has at least 317,000 SNPs distributed across the genome. Newest: ~1 million

38
Q

How do we sequence the whole genome using a few SNPs?

A

SNP-SNP association / linkage disequilibrium fundamental to our ability to sample whole genome with relatively few SNPs

Don’t directly measure genotypes at all genetic polymorphisms; rely on association between assayed polymorphisms and those not assayed

39
Q

What is LD?

A

LD is defined as the difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association

40
Q

How often does linkage disequilibrium occur?

A

In general, LD between two SNPs decreases with physical distance as more likely to have recombination event between them

41
Q

What does extent of LD depend upon?

A

Extent of LD varies greatly depending on region of genome ie. recombination hotspots

42
Q

What is meant by a strong LD?

A

If LD strong, need fewer SNPs to capture variation in a region - cheaper and easier / quicker to analyse

43
Q

Where are SNPs commonly found?

A

SNPs predominantly found in non coding regions with little influence on protein function

44
Q

What is the significance of SNPs being found in non coding regions?

A

Relates to why SNP variations may differ amount of protein produced but not whether you have the protein or not altogether (seen in rare disease cases)

45
Q

Why is further analysis from SNP chips required to identify causal variant

A

Often the causal variant (responsible for the association signal at a locus) is not included on the SNP chips so further work is required to narrow down the region of association and identify the causal variant

46
Q

How does GWAS identify variants?

A

Variants associated with the disease/trait (or within the same haplotype as a variant associated with a disease), will be found at a higher frequency in cases than in controls

47
Q

What does a P-value show us?

A

A p-value indicates the significance of the association i.e. the probability that the allele is likely to be associated with the trait

48
Q

What is a manhattan plot?

A

GWAS results are often displayed in a Manhattan plot with -log10(p-value) plotted against the position in the genome.
Each dot represents the p-value for a particular SNP

49
Q

What is the P-value threshold for GWAS results?

A

A P-value threshold of 5 × 10−8 has become a standard for genome-wide association studies (GWAS) to correct for multiple testing – this is based on the assumption that every genetic variant tested is independent of the rest

50
Q

What will a P-value of 0.05 tell us about the gene variants?

A

If we set the p-value threshold for each test to be 0.05, by chance we will “find” about 5% of SNPs to be associated with the disease

51
Q

What is the Bonferroni correction?

A

If the number of tests (SNPs genotyped) is n, we set the threshold to be 0.05/n

52
Q

What are the 3 potential interpretations of an SNP being significantly associated with disease?

A

If you identify a SNP that is significantly associated with disease, there are three possibilities:
- There is a causal relationship between SNP and disease
- The markers in linkage disequilibrium with a causal locus
= False positive

53
Q

What are the short term goals of GWAS?

A
  • Identify genetic variants that explain differences in
    phenotype among individuals in a study population
  • Qualitative: disease status, presence/absence of
    congenital defect
  • Quantitative: blood glucose levels, % body fat, heart rate
54
Q

What is the purpose of further study on disease associated SNPs?

A

If association found, then further study can follow to:
- Understand the mechanism of action and disease
aetiology in individuals

  • Characterise relevance and/or impact in more general
    population
55
Q

What are the long term goals of GWAS?

A

To inform the process of identifying and delivering better prevention and treatment strategies

56
Q

What is the Wellcome Trust Case Control Consortium ?

A

Genome-wide association study of 14,000 cases of

seven common diseases and 3,000 shared controls

Genomics (20 decks)

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