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Y2 GENETICS IN MEDICINE > Multifactorial Disease > Flashcards

Multifactorial Disease Flashcards

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1
Q

What is meant when a genetic disorder is described as ‘Mendelian’?

A

It obeys Mendel’s laws of segregation The condition is either dominant, recessive or X-linked

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2
Q

What is meant when a genetic disorder is described as ‘complex’?

A

this tends to be used vaguely to describe something with an inherited but non-Mendelian component

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3
Q

What is meant when a genetic disorder is described as polygenic?

A

the disorder results from the action of alleles of multiple genes

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4
Q

What is meant when a genetic disorder is described as multifactorial?

A

it is the result of multiple factors, usually including both genetic and environmental factors

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5
Q

What test is used to identify whether multifactorial disease has a genetic component?

A

twin studies

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6
Q

What is the result that is looked for in twin studies to show that a disease has a genetic component?

A

genetic characters should have a higher concordance in monozygotic twins compared to dizygotic twins

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7
Q

Other than twin studies, what other method is used to determine whether multifactorial disease has a genetic component?

A

familial clustering this calculates lambda s (relative risk to second sibling)

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8
Q

What is meant by ascertainment bias?

A

when geneticists want to prove something is inherited, they look for large families where multiple people are affected there may be some families where only one person ins affected

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9
Q

How is lambda s calculated in familial clustering?

A

Take every individual known with the condition and look to see if their siblings have it See whether there is an increased risk in people who share half their genome, compared to the general population

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10
Q

What would it mean if the lambda s score for a sibling is 9?

A

the sibling of someone who has a condition is 9 times more likely to get the disease, compared to the general population

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11
Q

If an identical twin had a lambda s score of 48%, what does this say about the environmental influence?

A

there must be an environmental component influencing development of the disease the entire genome is shared with someone who has the disease, but there is only a 48% risk of contracting it

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12
Q

How are the phenotypes of multifactorial/polygenic conditions determined?

A

by the action of many genes at different loci

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13
Q

Genes with polygenic inheritance aren’t dominant or recessive, so how are they expressed?

A

the disease alleles are additive the more of them you have, the greater your risk of getting a condition some carry a bigger risk than others

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14
Q

What are examples of basic human traits with polygenic inheritance?

A
  1. blood pressure 2. head circumference 3. height 4. intelligence
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15
Q

Can polygenic conditions be inherited? What are they influenced by?

A

diseases tend to run in families but not in a mendelian fashion they are influenced by the environment

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16
Q

What are the 3 key symptoms of Alzheimer’s disease?

A
  1. inability to cope 2. loss of memory 3. brain damage
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17
Q

What is involved in the neurology of Alzheimer’s disease?

A

shrinkage of the brain there are tangles of b-amyloid protein in nerve fibres of the hippocampus

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18
Q

What is the lambda s for Alzheimer’s disease? What does this suggest?

A

lambda s is 3-10 this shows that it tends to run in families a sibling of someone with alzheimers is 3-10 times more likely to contract it than the general population

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19
Q

What are the 2 main categories of genes that may be involved in Alzheimer’s and give similar end stage symptoms?

A

presenilin 1 (PSEN1) and presenilin 2 (PSEN2) both encode novel transmembrane aspartyl-proteases with y-secreatase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein (APP) and NOTCH receptor proteins missense mutations in APP

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20
Q

What factor has a large effect on the age of onset of Alzheimer’s disease?

A

sequence variants at a polymorphic locus much of the effect is due to the apo-lipoprotein E (APOE) gene

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21
Q

What are the 3 haplotypes of APOE?

A

APOE*E2 APOE*E3 APOE*E4

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22
Q

What is the role of APOE?

A

it encodes a chaperone protein that helps to fold other proteins

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23
Q

How do the 3 haplotypes/polymorphisms of APOE vary from each other?

A

E2 has Cys at position 112 and 158 E3 has Cys at position 112 and Arg at position 158 E4 has Arg at position 112 and 158

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24
Q

An individual carrying which APOE polymorphism is less protected against Alzheimer’s and why?

A

APOE*E4 It is less effective at folding proteins, so the individual is more susceptible to Alzheimer’s Especially if they are homozygous for E4 at both alleles

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25
Q

What haplotype of the APOE gene confers a protective effect against Alzheimer’s?

A

E2 haplotype

26
Q

How does the risk of Alzheimer’s increase from a E2/E3 heterozygote to an E4/E4 homozygote?

A

risk for late onset AD increases from 20% to 90% the mean age of onset decreases from 84 to 68 years the risk is increased further if there is high blood pressure

27
Q

How would an allele that has a low frequency in the population but greatly increases the risk of a condition be identified?

A

through linkage analysis

28
Q

How would an allele that has a high frequency in the population but not a sever effect on disease development be identified?

A

through an association study

29
Q

What is involved in an association study?

A

take a large group of people who have a condition and a large group of controls look for differences between the cases and the controls this may be genetic differences or environmental

30
Q

What is the aim of a genetic association study?

A

to relate variation in human DNA sequence with a disease or trait

31
Q

In an association study, what is important to consider about the controls?

A

They must match the cases e.g. gender, ethnicity they must be a representative sample of the population

32
Q

What is a single nucleotide polymorphism (SNPs)?

A

a difference at a single nucleotide these are mostly diallelic

33
Q

Do all SNPs cause disease?

A

Some can cause disease (e.g. missense, nonsense mutations) Some can be non-causal markers that tag haplotypes

34
Q

What does association mapping detect that linkage does not?

A

linkage disequilibrium

35
Q

What is the principal behind linkage? How many markers are used for genome coverage?

A

it detects recombination events in family pedigrees 300-400 markers for genome coverage

36
Q

What is the principal behind association mapping? How many markers are used for genome coverage?

A

it exploits recombination events in past generations it uses unrelated population samples it uses 1 million markers for genome coverage

37
Q

What types of markers are used in linkage and association mapping?

A

linkage mapping uses very polymorphic loci association mapping uses bi-allelic markers (SNPs)

38
Q

When is it best to use either linkage or association mapping?

A

linkage mapping is powerful for rare variants association mapping is powerful for common variants

39
Q

What is meant by linkage disequilibrium?

A

There is an ancestral chromosome with mutation D Going forward 40 generations, the thousands of ancestors inherit mutation D and a bit of the chromosome from immediately around the susceptibility allele

40
Q

What does linkage equilibrium show about how disease bearing chromosomes are inherited?

A

most disease bearing chromosomes in a population are descended from one (or a few) ancestral chromosomes

41
Q

What are the drawbacks of using linkage equilibrium in population association studies?

A
  1. careful selection of the control group is essential 2. large numbers of cases are needed 3. association may depend on the population history
42
Q

What is the definition of linkage disequilibrium?

A

the non-random association of alleles at two or more loci

43
Q

When looking at blocks of DNA, what is significant about the number of variants that are usually found?

A

There can be millions of variants of the same DNA sequence But usually there are only a few common variants that are actually seen

44
Q

What is significant about the location of a SNP in a block of DNA?

A

At this point, there may be one of 2 combinations present The rest of the DNA sequence is the same in different individuals

45
Q

What is meant by a linkage disequilibrium “block”?

A

within each DNA block there has not been any crossover or recombination within recent human history

46
Q

How can a susceptibility allele be detected within a LD block?

A

One or two SNPs from each block are picked and genotyped If the susceptibility allele is within a particular block, this can be identified by just 2 SNPs

47
Q

What test is used between case’s and control’s SNPs to determine whether a susceptibility allele is present?

A

Chi squared test between cases and controls for each SNP within an LD block A signal is seen of varying size A peak in signal across a region denotes a susceptibility allele in that part of the chromosome

48
Q

What is a Manhattan plot?

A

It is a visualisation of the GWAS results

All the SNP results are plotted on one graph

49
Q

What are the x and y axis on a Manhattan plot?

A

The x-axis shows the position in the genome (chromosome number)

The y-axis shows the significance (-log10 of the p-value)

50
Q

What is the significance level on a Manhattan plot?

What is it called?

A

-log10 (5 x 10^8)

This is equivalent to 8 on the y axis

This is the Bonferroni correction

51
Q

What is the a level when correcting for multiple testing in GWAS?

A

the a level is the probability of rejecting the null hypothesis given that it is true and is most often set at 0.05 (5%)

52
Q

Why is the Bonferroni correction needed?

A

Setting an a level of 0.05 for a single test is reasonable

If multiple tests are conducted, the probability of getting at least one significant result is large

The Bonferroni correction sets the significance cut-off at a/n

53
Q

What is the drawback of the Bonferroni correction?

A

It assumes that all tests are independent of one another

This is often not the case in genetics - e.g. testing multiple SNPs across one gene with strong linkage

54
Q

What is meant by indirect association as a reason for genotype disease association?

A

the locus is in linkage disequilibrium with a causal/functional variant

this means there are multiple SNPs near to the actual susceptibility allele

55
Q

What is meant by direct association as a reason for genotype disease association?

A

The locus is a causal/functional variant

This means that the gene you are testing carries the susceptibility allele

56
Q

What types of errors may give a reason for genotype disease association?

A
  1. spurious association Type I error - the chance of finding a susceptibility allele due to multiple testing
  2. population stratification
  3. systematic error - cases and controls are genotyped differently
57
Q

If a strong signal for genotype disease association is found, what should be done to confirm this?

A

It should be replicated in a different cohort

If the same signal is found, this is strong evidence that it is a susceptibility allele

58
Q

What is age-related macular degeneration?

A

it is the leading cause of irreversible central visual dysfunction caused by degeneration of the macula

59
Q

What is age-related macular degeneration characterised by?Early

A

The early deposition of drusen (spots on the fovia)

The patient loses their central vision and colour vision and are left only with peripheral vision

60
Q

What are the major 2 genetic changes involved in age-realated macular degeneration?

A

CFH on the long arm of chromosome 1

ARMS2 on the long arm of chromosome 10

61
Q

What environmental factors can influence development of age-related macular degeneration?

A

Smoking has a major effect

Light exposure can also affect this

Carrying high-risk alleles and smoking means you are 70 times more likely to get AMD

Y2 GENETICS IN MEDICINE (11 decks)

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