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Core Lectures > Identifying Genetic Causes of Disease > Flashcards

Identifying Genetic Causes of Disease Flashcards

1
Q

Why is it important to understand how disease is inherited?

A

For genetic testing and counselling

For risk prediction

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2
Q

Why is it important to elucidate the molecular basis of disease?

A

To identify drug targets
For ‘personalised medicine’
For gene therapy

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3
Q

Define allele

A

A version of a gene

Humans are diploid so have two alleles

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4
Q

Define homozygous

A

Two copies of the same allele (AA or aa)

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5
Q

Define heterozygous

A

Two copies of different alleles (Aa)

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6
Q

Define hemizygous

A

The state when only one allele is present

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7
Q

Define autosomal inheritance

A

A trait carried on one of the autosomes (non sex chromosome)

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8
Q

Define sex-linked inheritance

A

A trait carried on either the X or Y chromosome

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9
Q

Define mitochondrial inheritance

A

A trait carried within the mitochondrial (non nuclear) DNA and is maternally inherited

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10
Q

Define monogenic trait

A

Alterations to one gene causes phenotype

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11
Q

Define polygenic trait

A

More than one gene determines phenotype

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12
Q

Define multifactoral/complex trait

A

More than one gene determines phenotype and environmental factors may also have a role

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13
Q

Define dominance

A

Only one copy of an allele is required to cause a phenotype (heterozygous and homozygous individuals are affected)

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14
Q

What does a solid shape in a pedigree indicate?

A

An affected indivual

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15
Q

Define incomplete penetrance

A

Where individuals who have the ‘faulty’ copy of the gene do not display the disease or phenotype
This can show as skipped generations in pedigree analysis

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16
Q

Give an example of a codominant trait

A

Human blood group

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17
Q

Define codominance

A

Both phenotypes are expressed

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18
Q

What can monogenic traits be seen by?

A

Pedigree analysis

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19
Q

What type of inheritance do monogenic traits follow?

A

Simple Mendelian inheritance

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20
Q

How can you tell if a disease is genetically determined?

A

See if the disease runs in families

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21
Q

What can we deduce about parents if an affected individual has an autosomal dominant disease?

A

They must have at least one affected parent

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22
Q

What percentage of offspring will be affected if a parent has an autosomal dominant disease?

A

Approx. 50%

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23
Q

What is the ratio of males and females affected by an autosomal dominant disease?

A

Equal

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24
Q

Both males and females can transmit an autosomal dominant phenotype to their offspring, true or false?

A

True

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25
Q

What percentage of offspring are unaffected when both parents are heterozygous and affected by an autosomal dominant disease?

A

~25%

26
Q

What percentage of offspring are affected when both parents are heterozygous and affected by an autosomal dominant disease?

A

~75%

27
Q

What percentage of offspring have one copy of the dominant allele when both parents are heterozygous and affected by an autosomal dominant disease?

A

~50%

28
Q

What percentage of offspring have two copies of the dominant allele when both parents are heterozygous and affected by an autosomal dominant disease?

A

~25%

29
Q

For a carrier and unaffected parent of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A

50% unaffected

50% carrier

30
Q

For an affected and unaffected parent of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A

100% carrier

31
Q

When both parents are carriers of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A

50% carrier
25% affected
25% unaffected

32
Q

X-linked recessive diseases have the same principle as autosomal recessive diseases, but what else should be considered?

A

The inheritance restrictions of sex chromosomes

Males only have one copy of X so will show the recessive phenotype

33
Q

For an affected father and carrier mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A 
Females:
~50% affected
~50% carrier
Males:
50% affected
50% unaffected
34
Q

For an unaffected father and carrier mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A 
Females:
~50% unaffected
~50% carrier
Males:
50% affected
50% unaffected
35
Q

For an unaffected father and affected mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?

A

Females:
100% carrier
Males:
100% affected

36
Q

List the types of genetic variation

A

Chromosomal abnormality, e.g. translocations, trisomy
SNPs (single/simple nucleotide polymorphisms), e.g. A to T
Copy number variation (CNV)
Indels (insertions or deletions)

37
Q

What is the candidate gene approach for identifying genetic causes of disease?

A

Look for/type variants in gene regions where known biology predicts involvement
Sequence (whole genome or exome) genes

38
Q

What is the downside to the candidate gene approach for identifying genetic causes of disease?

A

It is biased as it relies on prior knowledge of disease biology

39
Q

What do regional association plots show?

A

The linkage relationship between SNPs

40
Q

How can the location of a SNP influence disease?

A

Could be…
In a coding region (changes protein produced)
Intronic (splicing)
In a regulatory region (promoter, enhancer)

41
Q

Do common diseases often run in families?

A

Yes

42
Q

Do complex traits follow Mendelian ratios of inheritance?

A

No

43
Q

How many genes are involved in complex traits?

A

Multiple

44
Q

Complex traits are purely genetic, true or false?

A

False, they also have environmental determinants

45
Q

What is now the most common method for investigating the genetic basis of complex diseases?

A

Genome-wide association studies (GWAS)

46
Q

Why is GWAS unbiased?

A

Because the whole genome is tested

47
Q

What does GWAS allow the discovery of?

A

Genetic regions with previously unknown disease biology

48
Q

What do modern GWAS arrays type individuals for?

A

SNPs, indels and CNVs

49
Q

How many variants per individual have been identified using GWAS arrays and imputation?

A

~10 million

50
Q

How can you analyse the genes that may potentially be involved with a disease?

A

Using case-control analysis

51
Q

What is the basis for case-control analysis?

A

Compare individuals with the disease (case) to healthy individuals (control)

52
Q

What is the standard threshold for genome-wide significance and what is this based on?

A

p < 5E-8

Based on Bonferroni correction for 1 million independent tests

53
Q

What is the false discovery rate for genome-wide significance?

A

1% or 5%
FDR 0.01 - 1 in every 100 loci incorrect
FDR 0.05 - 5 in every 100 loci incorrect

54
Q

How many variants is genome-wide significance testing?

A

Millions of variants across thousands of people

55
Q

Why do you need to control for multiple testing of genome-wide significance?

A

To reduce false positive results

56
Q

How does the location of the gene influence disease?

A

Most disease associated SNPs affect genes in close proximity (~200kb)

57
Q

How does the location of the SNP influence disease?

A

Knowing/predicting which SNP is having the effect can help identify the gene involved

58
Q

What questions can bioinformatics analysis answer to help predict the function of a SNP?

A

Is a protein coding change deleterious to protein function?
Is a transcription factor binding site altered?
Is there evidence of changes in gene expression linked to the SNP?

59
Q

Why is bioinformatics analysis helpful?

A

As there is an increasing amount of publically available data and online tools

60
Q

Understanding how a disease is inherited can help identify whether it is…

A

Monogenic or complex

61
Q

GWAS is a common and unbiased approach now widely used to identify genetic causes of disease, true or false?

A

True

62
Q

What does GWAS help us to identify about a disease?

A 
Risk prediction
Biological mechanisms involved
Personalised medicine (in the future)

Core Lectures (13 decks)

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