Genetic Basis of Multifactorial Disease Flashcards
what is polymorphism?
- any variation in human genome with population frequency >1%
OR - any variation in human genome that doesn’t cause a disease in its own right
- may however predispose common disease i.e. risk factor
quantitative inheritance
complex disorders and continuous traits are influenced by multiple genes and multiple environmental factors
single gene disorders vs complex traits
single gene: deterministic
complex traits: probabilistic
- even if they have all the susceptibility alleles, disease still depends on whether they encounter certain environmental hazards
liability
all the factors which influence the development of a multifactorial trait/disorder
what side of the threshold line represents those with a disorder?
right side
population incidence
proportion beyond threshold in general population where ‘abnormal phenotype’ is expressed
familial incidence
proportion beyond threshold among relatives where ‘abnormal phenotype’ is expressed
heritability of trait/disease
the proportion of the total variance that is genetic
mutation
a gene change that causes a genetic disorder
how to find out if there isa genetic contribution to a disease?
- family studies
- twin studies
what are downsides of family studies?
does not take into account a risk caused by a shared environment (e.g familial predilection for burgers in siblings)
what will happen to liability curve of affected and their relatives?
shift to the right; so familial incidence is higher than general population incidence
polygenic threshold characters
tend to run in families because affected individuals have relatives who share their genes with them
monozygotic vs dizygotic twins
- for a disease with a genetic contribution you would expect a monozygotic twin to be affected more frequently than a dizygotic twin
- this doesn’t take into account the possibility that being a monozygotic twin itself predisposes to disease
ways to know if a disease phenotype has genetic contribution to its causation
- recurrence risk in siblings
- twin studies
what are potential problems with association studies?
how do you know which gene to look at?
- disease may be influenced by 1 or 1000 genes
how do you which polymorphism to look at?
- 10-12 million in human genome
significant association may be true
significant association may be false and due to chance
significant association may be false due to population stratification - control group has to match affected group otherwise apparent true associations may be due to ethnic genetic difference between two groups, not disease
family history of common disease
- may suggest inherited predisposition
- more affected members
- people affected at a younger age
- may be caused by single mutation inherited in mendelian fashion but rare
- more likely to be caused by mixture of genetic and environmental factors (multifactorial)
predicting risk of heart disease
complex interaction: many environment and genetic factors
empirical risk estimates based on:
- cholesterol
- blood pressure
- diabetes
- smoking
- genetic tests have limited role (LDL receptor mutations)
treatment is based on clinical parameters
cleft lip empirical recurrence risks
population risk: 1/1000
sibling with unilateral cleft lip: 1/50
sibling with bilateral cleft lip: 1/20
second degree relative with cleft lip: 1/150
multifactorial conditions
exclude single gene/syndromic forms (rare)
higher recurrence risk if:
- more affected family members
- more severely affected family members
risk of recurrence data is calculated empirically - gene tests rarely help unless there is a monogenic form of disease
