Identifying Genetic Causes of Disease

Question 1

Why is it important to understand how disease is inherited?

Answer 1

For genetic testing and counselling

For risk prediction

Question 2

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

Answer 2

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

Question 3

Define allele

Answer 3

A version of a gene

Humans are diploid so have two alleles

Question 4

Define homozygous

Answer 4

Two copies of the same allele (AA or aa)

Question 5

Define heterozygous

Answer 5

Two copies of different alleles (Aa)

Question 6

Define hemizygous

Answer 6

The state when only one allele is present

Question 7

Define autosomal inheritance

Answer 7

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

Question 8

Define sex-linked inheritance

Answer 8

A trait carried on either the X or Y chromosome

Question 9

Define mitochondrial inheritance

Answer 9

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

Question 10

Define monogenic trait

Answer 10

Alterations to one gene causes phenotype

Question 11

Define polygenic trait

Answer 11

More than one gene determines phenotype

Question 12

Define multifactoral/complex trait

Answer 12

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

Question 13

Define dominance

Answer 13

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

Question 14

What does a solid shape in a pedigree indicate?

Answer 14

An affected indivual

Question 15

Define incomplete penetrance

Answer 15

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

Question 16

Give an example of a codominant trait

Answer 16

Human blood group

Question 17

Define codominance

Answer 17

Both phenotypes are expressed

Question 18

What can monogenic traits be seen by?

Answer 18

Pedigree analysis

Question 19

What type of inheritance do monogenic traits follow?

Answer 19

Simple Mendelian inheritance

Question 20

How can you tell if a disease is genetically determined?

Answer 20

See if the disease runs in families

Question 21

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

Answer 21

They must have at least one affected parent

Question 22

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

Answer 22

Approx. 50%

Question 23

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

Answer 23

Equal

Question 24

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

Answer 24

True

Question 25

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

Answer 25

~25%

Question 26

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

Answer 26

~75%

Question 27

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

Answer 27

~50%

Question 28

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

Answer 28

~25%

Question 29

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

Answer 29

50% unaffected | 50% carrier

Question 30

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

Answer 30

100% carrier

Question 31

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

Answer 31

50% carrier 25% affected 25% unaffected

Question 32

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

Answer 32

The inheritance restrictions of sex chromosomes | Males only have one copy of X so will show the recessive phenotype

Question 33

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

Answer 33

``` Females: ~50% affected ~50% carrier Males: 50% affected 50% unaffected ```

Question 34

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

Answer 34

``` Females: ~50% unaffected ~50% carrier Males: 50% affected 50% unaffected ```

Question 35

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

Answer 35

Females: 100% carrier Males: 100% affected

Question 36

List the types of genetic variation

Answer 36

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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

What do regional association plots show?

Answer 39

The linkage relationship between SNPs

Question 40

How can the location of a SNP influence disease?

Answer 40

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

Question 41

Do common diseases often run in families?

Answer 41

Yes

Question 42

Do complex traits follow Mendelian ratios of inheritance?

Answer 42

No

Question 43

How many genes are involved in complex traits?

Answer 43

Multiple

Question 44

Complex traits are purely genetic, true or false?

Answer 44

False, they also have environmental determinants

Question 45

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

Answer 45

Genome-wide association studies (GWAS)

Question 46

Why is GWAS unbiased?

Answer 46

Because the whole genome is tested

Question 47

What does GWAS allow the discovery of?

Answer 47

Genetic regions with previously unknown disease biology

Question 48

What do modern GWAS arrays type individuals for?

Answer 48

SNPs, indels and CNVs

Question 49

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

Answer 49

~10 million

Question 50

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

Answer 50

Using case-control analysis

Question 51

What is the basis for case-control analysis?

Answer 51

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

Question 52

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

Answer 52

p < 5E-8 | Based on Bonferroni correction for 1 million independent tests

Question 53

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

Answer 53

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

Question 54

How many variants is genome-wide significance testing?

Answer 54

Millions of variants across thousands of people

Question 55

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

Answer 55

To reduce false positive results

Question 56

How does the location of the gene influence disease?

Answer 56

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

Question 57

How does the location of the SNP influence disease?

Answer 57

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

Question 58

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

Answer 58

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?

Question 59

Why is bioinformatics analysis helpful?

Answer 59

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

Question 60

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

Answer 60

Monogenic or complex

Question 61

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

Answer 61

True

Question 62

What does GWAS help us to identify about a disease?

Answer 62

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