(4) Multifactorial disorders Flashcards
Define Mendelian
Obeys Mendel’s laws of segregation - dominant, recessive, X-linked
Define complex
Tends to be used vaguely to describe something with an inherited but non-Mendelian component
Define polygenic
The result of the action of multiple genes
Define multifactorial
The result of multiple factors, usually including both genetic and environmental factors
What does lambda s represent?
The risk to you when sibling has the condition, compared to risk to general population
Familial clustering (RELATIVE risk to 2nd sibling)
What is ascertainment bias?
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
Is schizophrenia hereditary?
Inherited but not Mendelian
How would you calculate lambda s?
The risk when sibling has the condition DIVIDED by the risk to the general population
If the risk of a condition is higher for fraternal twins that for siblings, what does this suggest?
Environment in the uterus has a big component
since siblings and fraternal twins share same amount of genome
What are MZ and DZ twins?
MZ = monozygotic (identical)
DZ = dizygotic (fraternal)
What does a much higher risk for MZ twins than DZ twins suggest?
Strong genetic component
What does a 48% risk to identical twin suggest?
Strong genetic component but also big environmental component
What is the basis of twin studies?
Genetic characters should have a higher concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins… but this does not automatically prove genetic effect
What is an issue with the reliability of twin studies?
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
What are 2 other problems with twin studies?
- assumption that the degree of environmental sharing is the same for MZ twins
- DZ twins can share more than half their genes
What is the basis of adoption studies?
- 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
Why are adoption studies difficult to perform in practice?
Because adoptions are becoming rare, and there are ethical issue about contacting the biological family
In polygenic/complex/multifactorial inheritance, phenotypes are determined by what?
By the action of many genes at different loci
Usually influenced by environment as well
In polygenic/complex inheritance, genes are what?
Additive, rather than dominant or recessive (additive = the more you have, the more you are at risk)
Give examples of multifactorial/polygenic traits/conditions
- blood pressure
- head circumference
- height
- intelligence
How are polygenic traits distributed?
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
Name some congenital malformations which show multifactorial inheritance
- cleft lip/palate
- congenital his dislocation
- congenital heart defects
- neural tube defects
- pyloric stenosis
- talipes
Name some acquired disease of childhood and adult life that show multifactorial inheritance
- asthma
- autism
- cancer
- diabetes mellitus
- epilepsy
- glaucoma
- hypertension
- IBD
- IHD and stroke
- bipolar disorder
- MS
- Parkinson disease
- psoriasis
- rheumatoid arthritis
- schizophrenia
50-70% of NTDs can be prevented by what?
Maternal folic acid supplementation 1 month before conception to 3 months after conception
What do genetic association studies seek?
Seek to relate variation in human DNA sequence with a disease or trait - estimated population attributable risk (effect size)
In a case-control study, controls should be what?
They should match cases (remove differences in ethnicity, age etc), and be representative of the population
How is an association found in a case-contol genetic association study?
Screen a gene is all of the cases and all of the controls and look for a difference
No statistically significant difference = no association
When mapping mendelian vs. multifactorial traits/diseases, what are the axes?
x axis = frequency in population
y axis = magnitude of effect
What studies are used for traits/genes that have high frequency in population but low magnitude of effect?
Association study
What studies are used for traits/genes that have low frequency in population but high magnitude of effect?
Linkage analysis
What type of alleles have low allele frequency but high effect size?
Rare alleles causing Mendelian disease
What is a SNP?
Single nucleotide polymorphism
- common, usually binary
- over 10 million identified
- easy and quick to test (can train computer to read)
What is linkage disequilibrium?
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
On a Manhattan plot, what do dots that are higher up on the y axis mean?
That that particular allele is more likely to be present in cases than controls - so that particular gene is significant
What does the thrifty phenotype hypothesis say?
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.
What are the symptoms of Alzheimer’s disease?
- inability to cope
- loss of memory
- brain damage
What is the neurology in Alzheimer’s disease?
- shrinkage of brain
- tangles of B-amyloid protein in nerve fibres of hippocampus
Early onset form of Alzheimer’s is now known to be what?
Genetically heterogeneous
Which genes are involved in the inherited form of Alzheimer’s disease?
- mutations in PSEN1 and PSEN 2 (presenilin)
- missense mutations in APP (amyloid precursor protein)
What do PSEN 1 and 2 encode?
Novel transmembrane aspartyl-proteases with y-secretase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein and NOTCH receptor proteins
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?
Apo-lipoprotein E (APOE) - a gene implicated in heart disease
What are the three haplotypes of APOE?
- APOE*E2
- APOE*E3
- APOE*E4
What codes for APOE-E2?
112 - cys
158 - cys
What codes for APOE-E3?
112 - cys
158 - arg
What codes for APOE-E4?
112 - arg
158 - arg
What does the APOE-E4 haplotype confer?
Increase in susceptibility of Alzheimer’s disease
What does the APOE-E2 haplotype confer?
Protective effect against Alzheimer’s disease
What happens to E4/E4 homozygotes compared to heterzygotes?
They are affected by Alzheimer’s disease much earlier than heterozygotes
Describe the differences between someone with E2/E3 and someone with E4/E4
- 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
What is the leading cause of irreversible central visual dysfunction/leading cause of blindness in the western world?
Age-related macular degeneration
Age-related macular degeneration is characterised by what?
Early deposition of drusen, a hallmark risk factor for AMD
What type of genetic condition is AMD?
Multifactorial
What are the 2 genes that have major effect on AMD?
- CFH (1q)
- ARMS2 (10q)
Which genes have intermediate effects on AMD?
- CFB/C2
- CFC3
What are the environmental factors in AMD?
Major effect = smoking
Intermediate effect = light exposure
Give 4 examples of polygenic diseases
- schizophrenia
- type II diabetes
- Alzheimer’s disease
- age-related macular dystrophy
