Multifactorial Inheritance

Question 1

What is the difference between a multifactorial and polygenic trait?

Answer 1

Multifactorial - includes environmental factors and other triggers, as well as genetic influence
Polygenic - includes only the additive effect of several unspecified genes, no environmental

Question 2

How are continuous or quantitative traits distributed, and what is considered abnormal?

Answer 2

Measured with a normal curve, abnormal is greater than 2 standard deviations from the mean

Question 3

What model is used to graph qualitative traits, and what is an example of variable expressivity?

Answer 3

The multifactorial threshold mold, which graphs if traits are present or absent. Variable expressitivity can show the degree of severity a particular trait is, for instance unilateral vs bilateral cleft lip

Question 4

At what point on the multifactorial threshold model will individuals have a particular trait?

Answer 4

There is a susceptibility based on number of genes which add to cause a particular condition. Once the threshold of liability is passed, individuals will be susceptible to have a trait

Question 5

How is the multifactorial threshold model changed according to sex (if one has higher incidence than the other) or there is another first degree relative affected with the condition?

Answer 5

Sex: if males have higher incidence than females, their threshold will be lower

If a first degree relative is affected, the threshold will be unchanged but the entire curve will be shifted to the right (higher risk) as compared to normal distribution

Question 6

What is heritability?

Answer 6

A variable between 0-1 which measures if the variation in a trait within a group of people is due to genetics or the environment. Lower = less heritable

Question 7

How is heritability calculated for a continuous trait?

Answer 7

H2 = 2(MZ correlation coefficient - DZ correlation coefficient)

If monozygotic twins are more closely correlated than dizygotic twins, the trait is more heritable and this number will be higher. 0.5 is taken as the threshold for when something is considered highly heritable for not

Question 8

How is heritability calculated for a discontinuous trait?

Answer 8

Concordant vs Discordant. Concordant = the two twins share the trait (have or not). Discordant = one has and one does not.

If Concordance is 100% in MZ and 50% in DZ, highly likely it’s genetic

If there is greater concordance in MZ than DZ in general, there is likely a genetic component.

No difference or low concordance = probably environmental

Question 9

What is family aggregation?

Answer 9

When there are more cases of a given disorder in close relatives of a person than in control families

Question 10

What type of study is used to study family aggregation? What can this not rule out?

Answer 10

Case control studies

This cannot rule out environmental factors within the family are a major cause of disease

Question 11

What is relative risk and how is it calculated?

Answer 11

Relative risk is risk comparing two groups of people, most commonly a given family vs the general population. Commonly calculated in case control studies

Calculation:
Relative risk = (incidence in relatives of a proband)/(incidence in general population)

1 = no difference. Rarely will you have lower than 1

Question 12

What is the utility of adoption studies?

Answer 12

Can help show the genetic component of some diseases. Compare adopted children from a parent with schizophrenia to adopted children from a parent without schizophrenia, and see if the relative risk is higher.

Question 13

What is a GWAS? How does this work?

Answer 13

Genome Wide Association Studies. Compare groups of people with a disease to similar groups of people without a disease. See if there is a DNA sequence variation held in common between affected and control groups, and this single nucleotide polymorphism may be inherited with the disorder and correlated with it (not causative)

Question 14

If an SNP is not causative of the disease condition, what must exist to explain the findings of a GWAS?

Answer 14

Linkage disequilibrium -> the SNP is disproportionately inherited with a mutant allele (not independently assorting)

Question 15

If the risk of a multifactorial trait in the general population is 1/150, what is the approximate recurrence risk of this trait in a first degree relative of an affected individual? Second degree relative?

Answer 15

Approximately the square root, which is ~1/12

Second degree relatives can be ignored -> approach population risk

Question 16

What is empiric risk?

Answer 16

Risk derived from familial aggregation studies, not necessarily specific for a particular family

Question 17

Give two modifiers of recurrence risk?

Answer 17

1. It is higher with a greater number of affected relatives

2. The more severely affected the proband, the higher the recurrence risk (higher genetic liability)

Question 18

If males are more commonly affected than females for a condition, who is it at the greatest recurrence risk? What is an example of this condition?

Answer 18

Sons of affected mothers (they have the highest genetic susceptibility threshold and are yet still affected)

Example: Pyloric stenosis - hypertrophy and hyperplasia of smooth muscle leads to projectile vomiting

Question 19

What are the two most common neural tube defects?

Answer 19

1. Spina bifida - myelomeningocele
2. Ancephaly

Failure of neural tube to fuse in the 4th week of embryogenesis

Question 20

List the genetic etiologies of neural tube defects

Answer 20

1. Trisomy 18
2. Trisomy 13
3. Meckel-Gruber syndrome

Higher prevalence in certain ethnic groups

Question 21

What is a common teratogenic cause of neural tube defects?

Answer 21

Valproic acid - an anticonvulsant

Question 22

What is the recurrence risk for NTDs for 1st degree relatives?

Answer 22

3-5%, incidence in general population is 1/1000. If two siblings were affected, it goes up to 10%

Question 23

What are some environmental factors which can cause NTDs?

Answer 23

Diabetes, obesity, seasonal variation, folic acid deficiency, maternal valproid acid use

Question 24

What is used to detect NTDs?

Answer 24

1. Elevated alpha-fetoprotein in maternal serum
2. Amniocentesis, checking acetylcholinesterase levels
3. Ultrasound