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genetics of human disease > GWAS > Flashcards

GWAS Flashcards

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1
Q

looking at the threshold model for multifactorial disease: if individuals cross the threshold they will have what?

A

combination of increased number of risk alleles or increased number of environmental risk factors

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2
Q

the relative contribution of each locus to overall population depends on:

A

magnitude of the effect of the risk allele
allele frequency
dominance
epistasis

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3
Q

risk alleles may be

A

common but have a small effect
rare with a large effect
mixture of oligogenes modified by polygenes and modifiers

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4
Q

effect size determines ease of what

A

identification or mapping

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5
Q

only a small proportion of individuals with the at risk genotype may suffer from the disease T/F

A

T

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6
Q

there are only a small number of alleles that are associated with a large risk of a complex disease. which locus and mutation is associated with type 1 diabetes

A

HLA locus

DQβ1 asp57any

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7
Q

if individuals are homozygous for which allele they are mmore likely to get alzheimers

A

ApoE ε4

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8
Q

what is an SNP

A

variation in a single nucleotide that occurs at a specific position in the genome

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9
Q

if you compared any 2 genomes you would find a difference around ever how many bases

A

1kb

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10
Q

in a population comparison with multiple genomes you would expect a difference every…

A

300bp

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11
Q

how many common SNPs are there

A

15million

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12
Q

how do we measure the effect sizes of alleles

A

Odds ratio

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13
Q

how do we calculate the odds ration (OR)

A

(cases/non cases genotype1) / (cases/non cases genotype2)

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14
Q

an odds ratio less than 1 indicates

A

condition is less likely to occur with the the first genotype

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15
Q

an odds ratio of more than 1 indicated

A

condition is more likely to occur with the the first genotype

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16
Q

what is genotype relative risk (GRR)

A

the ratio of risk with the allele compared to without the allele

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17
Q

what is the difference between OR and GRR

A

Relative risk is a ratio of probabilities whereas odds ratio is a ratio of odds

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18
Q

OR can overestimate and magnify risk, especially when the disease is more common (eg, hypertension) and should be avoided in such cases if RR can be used. T/F

A

T

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19
Q

what are the steps for conducting a GWAS

A
  • collect datasets of cases and controls
  • genotype each subject with a genome wide panel of SNPs
  • calculare the OR for each allele in the panel for each individual in the dataset
  • for each allele in genome wide panel - is the OR significantly different in cases and controls
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20
Q

if the OR is significantly different in cases compared to controls you can conclude

A

such alleles are associated with the disease

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21
Q

what are the 2 reasons of why an allele can be associated with a disease

A

1) the allele causes the risk

2) the allele is correlated with the causative allele because of linkage disequilibrium

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22
Q

which is more common

1) the allele causes the risk
2) the allele is correlated with the causative allele because of linkage disequilibrium

A

more common to be in linkage disequilibrium

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23
Q

what are haplotype blocks

A

set of closely linked alleles/markers on a chromosome that, over evolutionary time, tend to be inherited together

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24
Q

haplotype blocks mean that we can use one tag and easily work out the intervening sequences T/F

A

T

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25
Q

how can we work out the intervening sequences

A

because of linkage disequilibrium in haplotype blocks

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26
Q

the HapMap project was an international consortium that did what

A

used commercial microarrays to map haplotype blocks in the human genome

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27
Q

what do you use the map of haplotype blocks for

A

to select panel of SNPs that effectively stand as proxy for all other SNPs across genome

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28
Q

in GWAS you can get type 1 false positives - what does this mean

A

each SNP as individual test p value of 0.05 means the result would occur less than 1 in 20 times by chance. as you test more SNPs there will be more false positives

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29
Q

to get genome wide significance you need a p value of equal to or less than what

A

10^-8

30
Q

what is a type 2 false negative

A

set threshold too high (v small p value) and miss weak signals

31
Q

what is the “missing heritability” problem

A

he fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes

32
Q

where is the missing heritability

A
  • moderately rare alleles with moderate effect
  • polygenic model of inheritance (each allele has effect too small to be detected by GWAS)
  • overestimation of additive heritability in twin studies
33
Q

when the p value was relaxed in a GWAS for schizophrenia there were more alleles of significance what does that mean

A

evidence that statistics can cause genuine alleles ti fall short of significance in original study

34
Q

what is pathway analysis

A

seeing if the hits make biologiccal sense eg genes coding for muscle in lung in respiratory diseases

35
Q

if you look at possible number of alleles contributing to a disease and relax the p value what do you get

A

get more alleles

36
Q

how has GWAS been useful

A
  • has illuminated mechanisms (T1D)
  • can be used to predict those at risk (BC)
  • tells you about genetic architecture of common diseases and phenotypic traits
37
Q

what causes type 1 diabetes

A

autoimmune destruction of insulin producing β cells in islets of Langerhan

38
Q

how can you diagnose children with type 1 diabetes

A

autoantibodies are detectable before onset

39
Q

how much heritability has been defined in type 1 diabetes

A

80%

40
Q

50% of heritability in type one diabetes was associated with which allele

A

HLA

41
Q

the other genes involved in heritability of type 1 diabetes were what kind of genes

A

immune related genes involved in antigen presentation

42
Q

tolerance to insulin is established by neonatal tolerance to what

A

cytotoxic T cells that recognise insulin

43
Q

if there is a cytotoxic T cell that recognises self (eg insulin) during neonatal period it is directed to which pathway

A

apoptopic

44
Q

mutation in antigen presenting pathway - particularly in which genes cause the body to see insulin as foreign

A

BQb1 or IL2R

45
Q

mutation in antigen presenting pathway causes which cells to be destroyed so no insulin is produced

A

pancreatic b-islet cells

46
Q

breast cancer has how much lifetime risk for women

A

8-12%

47
Q

name 2 diseases that are caused by alleles with a large risk

A

alzheimers

parkinsons

48
Q

BRCA1/2 acoounts for how much of the heritability of breast cancer

A

5%

49
Q

how much heritability does genes involved in DNA repair pathway acount for in breast cancer

A

15%

50
Q

how much of the heritability of breast cancer comes from common alleles

A

40%

51
Q

common alleles have a minor allele frequency of more than…

A

0.5

52
Q

average risk age for breast cancer is what

A

50

53
Q

what is the downside for screening for breast cancer early

A
  • there may be a risk of overtreatment and intervention

- abnormality may not have caused any problems if left untreated

54
Q

UK women are invited to mammography screeing at what age

A

47

55
Q

what are non modifiable risk factors

A

polygenic risk score, family history, age of menarche, age of first child, age of menopause

56
Q

what are modifiable risk factors

A

BMI, HRT and smoking

57
Q

20% of preventable cancer would be avoided if the top 10% at risk adopted a healthy lifestyle T/F

A

T

58
Q

women in the top decile of non modifiable risk factors would have the same risk as an average women if they decreased modifiable risk factors T.F

A

T

59
Q

what is the interstitial model proposed by R.A fisher

A

As the number of genes grows very large, the

contribution of each gene becomes correspondingly smaller,

60
Q

what largely accounts for the missing heritability of many traits

A

SNPs with effect sizes well below the genome wide statistical significance

61
Q

what contributes to the missing heritability for diseases with major fitness consequences such as autism and schizophrenia

A

rare variants with larger effect sizes

62
Q

what is often thought of as the quintessential polygenic trait

A

height

63
Q

most ….. windows in the genome include variants that affect height

A

`100kb

64
Q

genetic contribution to disease is heavily concentrated in regions that are

A

transcribed or marked by active chromatin in relative tissues

65
Q

broadly functional categories contribute more total heritabiltiy than do genes in apparently disease relevant functional categories T/F

A

T

66
Q

for schizophrenia, chrohns and rheumatoid arthritis, where where the largest contributors to heritability found

A

in the broadest category genes - protein binding

67
Q

what are core genes

A

genes that have biologically interpretable roles in a disease

68
Q

give an example of a core gene

A

C4 on schizophrenia risk

69
Q

cell regulatory networks are highly connected meaning that any expressed gene is likely to effect the regulation or function of

A

core genes

70
Q

in summary what does the omnigenic model propose

A

since core genes are largely outnumbered by peripheral genes, a large fraction of the total genetic contribution to a disease comes from peripheral genes that do not play direct roles in the disease

71
Q

In conclusion, our molecular genetic data strongly support a polygenic basis to schizophrenia that (1) involves common SNPs, (2) explains at least one-third of the total variation in liability, (3) is substantially shared with bipolar disorder, and (4) is largely not shared with several non-psychiatric diseases T/F

A

T

genetics of human disease (10 decks)

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