Block D Lecture 2: Complex Genetic Disorders Flashcards
What are 4 common characterisitcs of complex genetic disorders?
Answers Include:
Partiall genetic and partially heritable
Risk and susceptability of developing them, but developing them isn’t guarenteed
Multiple genes can cause illness across a population
Different combinations of these genes can cause illness in different individals / families
Familial forms of disease may be observed - indicate major gene effect but this may be unique to that specific family
Phenotyping problems with them - quantitative or descriptive?
(Slide 4)
What 3 things are required in order for us to be able to identify genes involved in complex genetic disorders?
A suitable population to study for your genetic order (+ their DNA)
An understanding of the genetic architecture of the disorder
A suitable method (based on the above point)
(Slide 6)
What does the term “genetic architecture” mean?
The underlying genetic basis of a trait or a disorder, encompassing the number, type, and interaction of genetic factors that contribute to its expression
(Slide 7)
What are 4 examples / ways of individuals you would study for identification of the genes involved in a complex genetic disorder?
Special cases referred to a consultant
Families with a high density of cases
Case vs healthy control cohorts
Non-selective whole population / isolates prospective studies
(Slide 7)
How can epidemiology and twin studies help us understand the genetic architecture of the disease we are studying?
Epidemiology is the study of how often diseases occur in different groups of people and why - can help us understand triggers
Twin studies help us understand the genetic contribution to illness (as opposed to the environmental)
(Slide 11)
What is a twin study?
A study used in genetics to determine the contributions of genetics vs the environment to a particular disease. They compare monozygotic (MZ, identical) twins and dizygotic (DZ, fraternal) twins to analyze how much variation in a trait can be attributed to genetic factors versus environmental influences
(Slide 13)
What is the difference between monozygotic twins and dizygotic twinss?
Monozygotic twins are twins which are derived from a single fertilized egg that splits into two embryos
Dizygotic twins are derived from two separate eggs fertilized by two separate sperm
(Identical vs non-identical twins)
(Slide 13)
Which are more likely to have a disease if the other twin has it, monozygotic or dizygotic twins?
Monozygotic
(Slide 13)
What is “relative risk”?
A ratio of the frequency in relatives of the affected person to the frequency in the general population
e.g if frequency in siblings of affected individuals = 6% and frequency in general population = 0.4% then relative risk (RR) = 6/0.4 = 15
(Slide 14)
What are the common disease, common variant and the rare variant hypotheses?
Common disease, common variant hypotheses: Suggests that common diseases are caused by common genetic variants in the population
Rare variant hypotheses: Suggests that rare diseases are driven by rare genetic variants or familial mutations
Basically the rarer the disease, the rarer the mutation which causes the disease
(Slide 15)
What are 4 methods which can be used to identify genes involved in a complex genetic disorder and what are the assumptions needed for these to be used?
- Linkage (like for simple genetic disorders) - assumes mutations are rare and in few genes
- Case-control association studies - assumes mutations are common, in many genes
- Cytogenetics / CNVs
- Resequencing and personal genetics
(2 above assume rare mutations in many genes)
(Slide 16)
What 3 genes were identified to contribute to alzheimers from familial samples?
Amyloid precursor protein gene (APP)
Presnilin 1 and 2 (PS1 and PS2)
(Slide 18)
What gene which contributes to alzheimers was identified through non-parametric linkage analysis?
ApoE gene
(Slide 19)
What is the ApoE gene and how is it associated with Alzheimer’s?
It codes a protein known as Apolipoprotein E which is involved in the metabolism of fats in the body of mammals.
It has 3 subtypes labelled ApoE2, ApoE3 and ApoE4, with ApoE4 being a high risk allele for late-onset alzheimer’s
(Slide 19)
How does the ApoE allele cause late-onset Alzheimer’s?
ApoE4 homozygotes begin depositing amyloid plaques from the age of 55, with patients experiencing symptoms of Alzheimer’s disease from ~65 years of age, mild cognitive impairment diagnosis happening ~ 72, a dementia diagnosis at ~74 and death ~ 77 years of age. This happens ~ 7-10 years earlier than in people with the ApoE4 allele
(Slide 20)
