Genetic Basis for Complex Diseases

Question 1

What is heritability?

Answer 1

proportion of phenotypic variability that can be attributed to genetic

traits that are largely determined by genes will have heritability approaching 1

Question 2

What is the term for traits that are either present or absent?

Answer 2

dichotomous

Question 3

Is risk a continuous spectrum?

Answer 3

Yes

Question 4

What happens to the risk curve of family members of affected people in comparison to the risk curve of the general population?

Answer 4

shift to the right. i.e. the potential to pass the threshold is elevated and they are at an elevated risk

Question 5

What aspects of family history influence risk of multifactorial disease?

Answer 5

1) Degree of relationship- drops off rapidly after immediate family
2) Number of affected family members
3) Severity of disease expression
4) Associated conditions in family members-i.e. atopy has an increased risk in association with asthma
5) age of relative at onset- younger onset= higher risk

Question 6

Are multifactorial diseases more or less common than mendelian diseases like CF and Huntington’s

Answer 6

more. risk is roughly 1 in 1000 for multifactoral diseases (rough number but a good basis)

Question 7

For multifactorial disease, is the associated risk of having a disease based on a immediate family member having the disease higher or lower than population risk?

Is it higher or lower than mendelian risk in a similar situation (i.e. one affected family member)

Answer 7

higher than population risk but still much lower than a similar situation with a mendelian disease

Question 8

What happens to the risk in a multifactorial disease when a 2nd degree family member is involved?

Answer 8

It drops rapidly (say from 4% in the 1st degree to 0.7% in the second)

this is different from mendelian which would only drop off by half (say from 4% to 2%)
due to a single further meiosis occurring

Question 9

When does the risk of a multifactoral disease based on family relationship drop to near population risk?

Answer 9

3rd degree of relation

Question 10

Does the threshold model address cause?

Answer 10

No.

Question 11

What happens to risk when more family members are affected by a multifactoral disease?

Answer 11

it goes up rapidly (say from 4% w/ 1 affected family member, 12% with 2, and 25% with three)

Question 12

Which have larger risks to relatives, mendelian or complex risk diseases?

Answer 12

mendelian

Question 13

Which are more common, mendelian or complex risk diseases?

Answer 13

complex risk diseases (think asthma vs CF)

Question 14

Which show more variability in symptoms, mendelian or complex risk diseases?

Answer 14

complex risk

Question 15

Which show younger onset of disease, mendelian or complex risk diseases?

Answer 15

mendelian

Question 16

For diabetes, which are a better predictor of risk, risk genes or phenotypic data?

Answer 16

phenotypic data

Question 17

What is the concept of ‘missing heritability’

Answer 17

complex diseases are very often impacted by risk genes (which are highly heritable) but they show little phenotypical correlation to the prevelance/risk of many diseases like diabetes

i.e. the highest risk gene for diabetes only increases risk by 30%

Question 18

What is the take home message of a Manolio graph?

Answer 18

alleles that are common in the population won’t show high penetrance or have that large of a detrmental impact, while rare alleles will show higher penetrance (i.e. CF)