Genetic Basis of Multifactorial Disease

Question 1

what is polymorphism?

Answer 1

• 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

Question 2

quantitative inheritance

Answer 2

complex disorders and continuous traits are influenced by multiple genes and multiple environmental factors

Question 3

single gene disorders vs complex traits

Answer 3

single gene: deterministic

complex traits: probabilistic
- even if they have all the susceptibility alleles, disease still depends on whether they encounter certain environmental hazards

Question 4

liability

Answer 4

all the factors which influence the development of a multifactorial trait/disorder

Question 5

what side of the threshold line represents those with a disorder?

Answer 5

right side

Question 6

population incidence

Answer 6

proportion beyond threshold in general population where ‘abnormal phenotype’ is expressed

Question 7

familial incidence

Answer 7

proportion beyond threshold among relatives where ‘abnormal phenotype’ is expressed

Question 8

heritability of trait/disease

Answer 8

the proportion of the total variance that is genetic

Question 9

mutation

Answer 9

a gene change that causes a genetic disorder

Question 10

how to find out if there isa genetic contribution to a disease?

Answer 10

• family studies

- twin studies

Question 11

what are downsides of family studies?

Answer 11

does not take into account a risk caused by a shared environment (e.g familial predilection for burgers in siblings)

Question 12

what will happen to liability curve of affected and their relatives?

Answer 12

shift to the right; so familial incidence is higher than general population incidence

Question 13

polygenic threshold characters

Answer 13

tend to run in families because affected individuals have relatives who share their genes with them

Question 14

monozygotic vs dizygotic twins

Answer 14

• 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

Question 15

ways to know if a disease phenotype has genetic contribution to its causation

Answer 15

• recurrence risk in siblings

- twin studies

Question 16

what are potential problems with association studies?

Answer 16

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

Question 17

family history of common disease

Answer 17

• 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)

Question 18

predicting risk of heart disease

Answer 18

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

Question 19

cleft lip empirical recurrence risks

Answer 19

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

Question 20

multifactorial conditions

Answer 20

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