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EMS - GiM > (4) Multifactorial disorders > Flashcards

(4) Multifactorial disorders Flashcards

1
Q

Define Mendelian

A

Obeys Mendel’s laws of segregation - dominant, recessive, X-linked

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2
Q

Define complex

A

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

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3
Q

Define polygenic

A

The result of the action of multiple genes

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4
Q

Define multifactorial

A

The result of multiple factors, usually including both genetic and environmental factors

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5
Q

What does lambda s represent?

A

The risk to you when sibling has the condition, compared to risk to general population

Familial clustering (RELATIVE risk to 2nd sibling)

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6
Q

What is ascertainment bias?

A

May only pick the families where an apparent dominant inheritance is shown, whereas really, this may just be a coincidence. You need to look at all families of every single case you’ve got

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7
Q

Is schizophrenia hereditary?

A

Inherited but not Mendelian

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8
Q

How would you calculate lambda s?

A

The risk when sibling has the condition DIVIDED by the risk to the general population

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9
Q

If the risk of a condition is higher for fraternal twins that for siblings, what does this suggest?

A

Environment in the uterus has a big component

since siblings and fraternal twins share same amount of genome

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10
Q

What are MZ and DZ twins?

A

MZ = monozygotic (identical)

DZ = dizygotic (fraternal)

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11
Q

What does a much higher risk for MZ twins than DZ twins suggest?

A

Strong genetic component

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12
Q

What does a 48% risk to identical twin suggest?

A

Strong genetic component but also big environmental component

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13
Q

What is the basis of twin studies?

A

Genetic characters should have a higher concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins… but this does not automatically prove genetic effect

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14
Q

What is an issue with the reliability of twin studies?

A

As well as sharing more of the genome, identical twins also share more of an environment (non-identical twins may have different amniotic sac and placenta etc) - so twin studies not a perfect test

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15
Q

What are 2 other problems with twin studies?

A
  • assumption that the degree of environmental sharing is the same for MZ twins
  • DZ twins can share more than half their genes
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16
Q

What is the basis of adoption studies?

A
  • child is put into totally different environment to its birth environment
  • compare its fate with that of its adoptive versus biological family
  • most often performed for psychiatric conditions
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17
Q

Why are adoption studies difficult to perform in practice?

A

Because adoptions are becoming rare, and there are ethical issue about contacting the biological family

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18
Q

In polygenic/complex/multifactorial inheritance, phenotypes are determined by what?

A

By the action of many genes at different loci

Usually influenced by environment as well

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19
Q

In polygenic/complex inheritance, genes are what?

A

Additive, rather than dominant or recessive (additive = the more you have, the more you are at risk)

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20
Q

Give examples of multifactorial/polygenic traits/conditions

A
  • blood pressure
  • head circumference
  • height
  • intelligence
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21
Q

How are polygenic traits distributed?

A

Tend to be normally-distributed in the general population ie. forms a Gaussian “bell-shaped curve” with even distribution about a mean

Diseases tend to ru in families but not in a simple Mendelian fashion

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22
Q

Name some congenital malformations which show multifactorial inheritance

A
  • cleft lip/palate
  • congenital his dislocation
  • congenital heart defects
  • neural tube defects
  • pyloric stenosis
  • talipes
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23
Q

Name some acquired disease of childhood and adult life that show multifactorial inheritance

A
  • asthma
  • autism
  • cancer
  • diabetes mellitus
  • epilepsy
  • glaucoma
  • hypertension
  • IBD
  • IHD and stroke
  • bipolar disorder
  • MS
  • Parkinson disease
  • psoriasis
  • rheumatoid arthritis
  • schizophrenia
24
Q

50-70% of NTDs can be prevented by what?

A

Maternal folic acid supplementation 1 month before conception to 3 months after conception

25
Q

What do genetic association studies seek?

A

Seek to relate variation in human DNA sequence with a disease or trait - estimated population attributable risk (effect size)

26
Q

In a case-control study, controls should be what?

A

They should match cases (remove differences in ethnicity, age etc), and be representative of the population

27
Q

How is an association found in a case-contol genetic association study?

A

Screen a gene is all of the cases and all of the controls and look for a difference

No statistically significant difference = no association

28
Q

When mapping mendelian vs. multifactorial traits/diseases, what are the axes?

A

x axis = frequency in population

y axis = magnitude of effect

29
Q

What studies are used for traits/genes that have high frequency in population but low magnitude of effect?

A

Association study

30
Q

What studies are used for traits/genes that have low frequency in population but high magnitude of effect?

A

Linkage analysis

31
Q

What type of alleles have low allele frequency but high effect size?

A

Rare alleles causing Mendelian disease

32
Q

What is a SNP?

A

Single nucleotide polymorphism

  • common, usually binary
  • over 10 million identified
  • easy and quick to test (can train computer to read)
33
Q

What is linkage disequilibrium?

A

40 generations later, affected individuals will carry the original mutation of the ancestral chromosome as well as the same 1 million base pairs in the region surrounding the mutation - the mutation and surrounding variants have “hitchhiked” through the generations

34
Q

On a Manhattan plot, what do dots that are higher up on the y axis mean?

A

That that particular allele is more likely to be present in cases than controls - so that particular gene is significant

35
Q

What does the thrifty phenotype hypothesis say?

A

Reduced foetal growth is strongly associated with a number of chronic conditions later in life. This increased susceptibility results from adaptations made by the foetus in an environment limited in its supply of nutrients.

36
Q

What are the symptoms of Alzheimer’s disease?

A
  • inability to cope
  • loss of memory
  • brain damage
37
Q

What is the neurology in Alzheimer’s disease?

A
  • shrinkage of brain

- tangles of B-amyloid protein in nerve fibres of hippocampus

38
Q

Early onset form of Alzheimer’s is now known to be what?

A

Genetically heterogeneous

39
Q

Which genes are involved in the inherited form of Alzheimer’s disease?

A
  • mutations in PSEN1 and PSEN 2 (presenilin)

- missense mutations in APP (amyloid precursor protein)

40
Q

What do PSEN 1 and 2 encode?

A

Novel transmembrane aspartyl-proteases with y-secretase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein and NOTCH receptor proteins

41
Q

Sequence variants at a polymorphic locus have a large effect on age of onset of Alzheimer’s disease. Much of the effect is due to what?

A

Apo-lipoprotein E (APOE) - a gene implicated in heart disease

42
Q

What are the three haplotypes of APOE?

A
  • APOE*E2
  • APOE*E3
  • APOE*E4
43
Q

What codes for APOE-E2?

A

112 - cys

158 - cys

44
Q

What codes for APOE-E3?

A

112 - cys

158 - arg

45
Q

What codes for APOE-E4?

A

112 - arg

158 - arg

46
Q

What does the APOE-E4 haplotype confer?

A

Increase in susceptibility of Alzheimer’s disease

47
Q

What does the APOE-E2 haplotype confer?

A

Protective effect against Alzheimer’s disease

48
Q

What happens to E4/E4 homozygotes compared to heterzygotes?

A

They are affected by Alzheimer’s disease much earlier than heterozygotes

49
Q

Describe the differences between someone with E2/E3 and someone with E4/E4

A
  • risk for late-onset AD increases from 20% to 90%
  • mean age of onset decreases from 84 to 68
  • risk is increased further if there is high blood pressure
50
Q

What is the leading cause of irreversible central visual dysfunction/leading cause of blindness in the western world?

A

Age-related macular degeneration

51
Q

Age-related macular degeneration is characterised by what?

A

Early deposition of drusen, a hallmark risk factor for AMD

52
Q

What type of genetic condition is AMD?

A

Multifactorial

53
Q

What are the 2 genes that have major effect on AMD?

A
  • CFH (1q)

- ARMS2 (10q)

54
Q

Which genes have intermediate effects on AMD?

A
  • CFB/C2

- CFC3

55
Q

What are the environmental factors in AMD?

A

Major effect = smoking

Intermediate effect = light exposure

56
Q

Give 4 examples of polygenic diseases

A
  • schizophrenia
  • type II diabetes
  • Alzheimer’s disease
  • age-related macular dystrophy

EMS - GiM (14 decks)

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