Complex Disease

Question 0

What percent of human disease is due to Mendelian disease?

Answer 0

1-4%

Question 1

What percent of human disease is due to chromosomal abnormalities?

Answer 1

<1%

Question 2

What percent of human disease is due to complex disease?

Answer 2

95%

Question 3

What are chromosomal abnormalities with relation to human disease?

Answer 3

Abnormalities resulting in visible alteration of chromosomes or resulting from specifically chromosomal mechanisms

Question 4

Chromosomal abnormalities can be constitutional or… ?

Answer 4

Somatic - i.e. not present in all cells

Question 5

What are numerical chromosomal abnormalities?

Answer 5

Alterations in the number of chromosomes, e.g. triploidy, tetraploidy and aneuploidy

Question 6

What do the terms triploidy and tetraploidy mean?

Answer 6

When an individual’s cells contain three or four copies of the whole genome (rather than two) - this is LETHAL

Question 7

How does triploidy/tetraploidy occur?

Answer 7

As a result of dispermy, diploid gamete or endomitosis

Question 8

What is aneuploidy?

Answer 8

When an individual has more or less copies of one or more chromosomes

Question 9

What is trisomy?

Answer 9

When an individual has an extra copy of one chromosome

e.g. Down’s Syndrome - extra copy of chromosome 21

Question 10

What is monosomy?

Answer 10

When an individual has one less copy of a chromosome

e.g. Turner’s Syndrome - one less X chromosome

Question 11

How is Mendelian disease defined?

Answer 11

A trait caused by a mutation in a single gene (i.e. monogenic) with a known pattern of inheritance

Question 12

In what case is a genotype at a locus both necessary and sufficient for a trait to be expressed?

Answer 12

Mendelian disease

Question 13

What factors can influence inheritance of Mendelian disease?

Answer 13

incomplete penetrance
locus heterogeneity 
allelic heterogeneity
clinical heterogeneity 
genetic anticipation 
genetic imprinting

Question 14

what is penetrance?

Answer 14

the proportion of individuals with a particular genetic mutation who exhibit signs of the mutation (i.e. the trait)

Question 15

what is locus heterogeneity?

Answer 15

mutations at many different loci (in many different genes) giving the same phenotype

Question 16

what is allelic heterogeneity?

Answer 16

different mutations in one gene giving the same phenotype

Question 17

what is clinical heterogeneity?

Answer 17

the same mutation giving different phenotypes

Question 18

what is genetic anticipation?

Answer 18

disease increasing in severity with each passing generation

Question 19

what is genetic imprinting?

Answer 19

when a different phenotype is seen depending on whether mutation was inherited from mother or father

Question 20

how can a genetically complex disease be defined?

Answer 20

a disease where one or more alleles acting alone or in concert increase or decrease the risk of developing a trait

Question 21

is genetically complex disease monogenic or polygenic?

Answer 21

genetically complex disease is usually polygenic, monogenic complex disease is very rare

Question 22

which shows higher penetrance, Mendelian or complex disease?

Answer 22

Mendelian disease - complex disease usually shows low penetrance (having the allele only increases the risk of disease)

Question 23

In what genetic inheritance is the presence of the susceptibility allele neither necessary nor sufficient to trait development?

Answer 23

Genetically complex inheritance

Question 24

what is disease prevalence?

Answer 24

the total number if cases at any given time

Question 25

what is disease incidence?

Answer 25

the number of new cases/unit of time

Question 26

how is sibling risk ratio calculated?

Answer 26

the incidence/prevalence in siblings divided by the incidence/prevalence in population

Question 27

How can the heritability of a genetic disease be assessed?

Answer 27

``` calculating sibling risk ratio family and twin studies segregation analysis linkage analysis association analysis (GWAS/GWLS) ```

Question 28

What are twin studies?

Answer 28

Disease concordance rates (degree of "trait sharing") compared in monozygotic and dizygotic twins

Question 29

What can twin studies show?

Answer 29

If concordance rate is higher in monozygotic twins compared to dizygotic twins, there is a significant genetic component

Question 30

What is a disadvantage of twin studies?

Answer 30

twins have a shared environment from birth therefore results may be influenced by environment

Question 31

how can a shared environment in twin studies be controlled for?

Answer 31

adoption studies looking at clustering of disease in biological vs. adoptive family

Question 32

what is concordance in genetics?

Answer 32

the presence of the same trait in two individuals

Question 33

What are two approaches to identifying susceptible alleles in complex disease?

Answer 33

Linkage and association analyses

Question 34

What is required to carry out a linkage analysis study?

Answer 34

the collection of DNA from informative families - i.e. family pedigrees or sibling pairs

Question 35

can DNA from monozygotic twins be used in linkage analyses?

Answer 35

no, as monozygotic twins have identical genes and alleles

Question 36

what is a LOD score?

Answer 36

a statistical estimate of whether two genes are located near each other on a chromosome and therefore are likely to be inherited together (i.e. the degree of LINKAGE of two genes)

Question 37

what is linkage of two genes defined as?

Answer 37

linkage is a measure of association between genes on the same chromosome - the closer the two genes are on the chromosome (i.e. the higher the degree of linkage) the more likely they are to be inherited together during meiosis

Question 38

How is a LOD score calculated?

Answer 38

via parametric linkage analysis

Question 39

what does a LOD score > 3 indicate?

Answer 39

Evidence for linkage between two genes i.e. the odds of the linkage observed NOT being due to chance is 1000 to 1

Question 40

what is linkage disequilibrium?

Answer 40

if two genes are in linkage disequilibrium, certain alleles of each gene are inherited together more often than would be expected by chance

Question 41

what is linkage equilibrium?

Answer 41

linkage equilibrium refers to two genes inherited completely independently in each generation - e.g. two loci on two different chromosomes that encode unrelated, non-interacting proteins

Question 42

what can genetic association studies show?

Answer 42

the statistical likelihood of developing a certain trait based on the presence of a certain allele

Question 43

what is the general difference between linkage analyses and association analyses?

Answer 43

linkage analyses are carried out in families, association analyses are carried out in a population

Question 44

what are advantages of genome-wide association analyses? (GWAS)

Answer 44

- can look at susceptibility alleles in sporadic and infectious disease - hypothesis-free therefore does not require previous knowledge of disease - can identify novel susceptibility loci/associated alleles

Question 45

how were GWAS carried out in the pre-genome era?

Answer 45

by searching for non-random segregation of variable number tandem repeats (VNTRs) or "microsatellites"

Question 46

what is the outcome of a GWAS?

Answer 46

an odds ratio (OR) score

Question 47

what does an odds ratio (OR) of p < 5x10-7 show in GWAS?

Answer 47

that the association between a particular SNP (allele) and phenotype is significant

Question 48

which two different alleles did two different studies identify as the primary susceptibility alleles for PBC?

Answer 48

HLA-DQA1*0401 and DRB1-08:01-DQ4 haplotype