L58: Genetic Basis Of Multifactorial Diseases

Question 1

Simple disease (Mendelian disease) vs Complex disease

Answer 1

Simple:
- genotype and phenotype closely correlated
- mutation CAUSE the disease
Complex:
- genotype and phenotype poorly correlated
- mutation PREDISPOSE the disease

Population frequency:
Low, rare, isolated pedigree
High, common, general population

Number of genes required to produce the phenotype:
One
Multiple

Penetrance / participation of individual genes:
High
Low

Environmental influence:
Low
High

Diagnosis / Patient ascertainment:
Family history
Medical screening

Method of detection:
Linkage analysis: detection of disease genes
Association studies / Genome association

Question 2

Models of Multifactorial disease

Answer 2

1. Common disease/ common variant: common disease alleles are found in all population
2. Polygenic model: genetic component of a quantitative trait is determined by large number of loci each contributing a small additive effect / many low frequency alleles can influence disease risk
3. Oligogenic model: only a few genes but each have predominant effect

Question 3

Relationship between quantitative traits and Multifactorial disease

Answer 3

Polygenic model explains quantitative traits (traits that are measured on a continuous numerical scale: follow normal distribution pattern)

Liability-threshold model: number of multifactorial genes ↑ —> liability ↑ —> over threshold —> disease state

Threshold explain dichotomous character of disease under polygenic model

Question 4

Basic assumption of liability-threshold model

Answer 4

1. All environmental and genetic causes can be combined into only single continuous variable normal distribution curve called liability
2. Numerous genetic and environmental factors act additively, each contributing a small amount of liability
3. Liability has a normal distribution
4. As soon as liability exceeds thresholds, individuals are affected

Question 5

ACE composition

Answer 5

Y (quantitative phenotype) = A (additive genetic effect) + C (common family environment) + E (individual environment)

1 = h^2 (heritability) + c^2 + e^2
—> every component will change depends on changes in other components

Heritability: indicate the % contribution of genes to differences in individuals

Question 6

How Family aggregation is measured

Answer 6

Recurrence risk ratio = Risk for family member of proband / Risk of general population

相對普羅大眾，有幾大機會其他家庭成員會有病

Mendelian traits:

• recurrence risk is the same regardless of how severely individual is affected
• recurrence risk is the same regardless of no. of affected family members
• recurrence risk drop proportionately with degree of relationship

Multifactorial traits:

• recurrence risk is higher in more severely affected individual due to more gene transmission
• recurrence risk is higher if more children are affected
• recurrence risk drop very quickly with the degree of relationship

Question 7

How to determine the susceptibility of an individual to a disease

Answer 7

1. Family aggregation
2. Heritability of disease
3. Any disease-marker relationship
4. Any alleles associated with increased risk of disease