Exam #5: Multifactorial Disorders

Question 1

How do you estimate the number of genes involved in the inheritance of a quantitative trait?

Answer 1

• More than one gene contributes to the phenotype
• 2 genes= 4 alleles, 3 genes= 6 alleles
• Each allele is contributing or noncontributing
• 2 genes= 0, 1, 2, 3, or 4 contributing alleles; thus, 5 different phenotypes

Question 2

How does a multifactorial pedigree differ from an autosomal dominant pedigree?

Answer 2

• Pedigrees of families with multifactorial disease do not show easily recognizable patterns
• Most closely resemble autosomal dominant with incomplete penetrance

Question 3

Why does the recurrence risk for a multifactorial disease change every time a relative is diagnosed with the disorder?

Answer 3

• It is usually not known how many contributing alleles there are in a parent generation
• Birth of each affected child allows for more & more accurate calculation of risk
• The more affected children there are, the higher assumed number of contributing alleles in the parent generation
• Thus every time an affected child is born, the recurrence risk has to be corrected upwards

Question 4

What are the gender-specific differences in recurrence risk for multifactorial disorders such as pyloric stenosis?

Answer 4

• Frequently the threshold of liability is different for males & females ( it is also influenced by environmental factors)
• 1/200 males affected vs. 1/1,000 females
• Lower threshold for males & higher threshold for females
• Thus, affected female is has more contributing alleles than affected male

Question 5

How are the genetic & environmental influences on complex diseases estimated?

Answer 5

• Twin studies & adoption studies

Question 6

How do you map multiple contributing alleles?

Answer 6

• Linkage analysis based on the assumption that relatives with the same disorder will have the same alleles in common
• Genome of sibling pairs is analyzed for the presence of shared SNPs
• Loci that are shared significantly more often that those expected by chance are likely to be involved in the etiology of the disease

Question 7

What are the statistical measures that describe the risk for multifactorial diseases in general populations?

Answer 7

• Disease association= quantifies how the allele in question influences the risk of the disorder

Question 8

Relative risk ratio

Answer 8

Prevalence of the disease in relative “r” of affected person/ prevalence in general populaiton

Question 9

HLA Haplotypes & DM-I

Answer 9

• MHC locus is found on chromosome 6
• MHC Class I & II encode cell surface proteins that initiate immune response
• These proteins are called human leukocyte antigens (HLA)
• HLA genes are highly polymorphic
• DR-DQ haplotypes are implicated in DM-1

Question 10

What are the most common genetic diseases?

Answer 10

1) Multifactorial
2) Single gene
3) Chromosomal

Question 11

Multifactoral Disease

Answer 11

Combination of polymorphic alleles that are not ideal for the current environment

Question 12

Quantitative Traits

Answer 12

Traits that can be measured such as height

Question 13

What is the likelihood that offspring will inherit a multifactorial disease if there are many genes involved? What if there are few genes?

Answer 13

• Low if many genes b/c there will be a lower fraction of extreme phenotypes
• Higher if few genes

Question 14

What is the bell curve of phenotype distribution in a population called in a multifactorial disease?

Answer 14

Liability Distribution, where disease results if the threshold of liability is crossed

Question 15

Pyloric Stenosis

Answer 15

• Area between the stomach & duodenum is narrowed

- Causes frequent vomiting & constipation

Question 16

Monozygotic twins

Answer 16

100% genetically identical (single fertilized egg)

Question 17

Dizygotic twins

Answer 17

50% genetically identical (simultaneous fertilization of two eggs by two sperm)

Question 18

Concordance Rate

Answer 18

How often a trait is shared by both individuals in a pair

Question 19

Heritability

Answer 19

• (Concordance MZ- Concordance DZ) x2
• High heritability indicates a strong genetic component
• Values should be between 0-1 (if not, must be other factors)

Question 20

Incidence

Answer 20

How many new cases are recorded in a given time, divided by the size of the population

Question 21

Prevalence

Answer 21

Proportion of the population that is affected by the disease at any given time

Question 22

What is the risk of developing a common birth defect in the general population?

Answer 22

0.5%

Question 23

What is the risk of developing a common birth defect if a second degree relative is affected?

Answer 23

• 0.7-2%

- 2-4x higher

Question 24

What is the risk of developing a common birth defect if a first degree relative is affected?

Answer 24

• 3-4%

- 6-8x higher

Question 25

What is the risk of developing a common birth defect if two first degree relatives are affected?

Answer 25

• 5-8%

- 10-16x higher

Question 26

What is the risk of developing a common birth defect if three first degree relatives are affected?

Answer 26

• 9-12%

- 18-24x higher

Question 27

What is the risk of developing a common birth defect if an identical twin is affected?

Answer 27

• 20-30%

- 40-60x higher

Question 28

What are the four characteristics of multifactorial diseases that set them apart from single-gene disorders?

Answer 28

1) Do not follow mendelian inheritance
2) Show familial aggregation
3) Incomplete penetrance
4) Disease is more common among close relatives than less closely related persons

Question 29

Susceptibility Alleles

Answer 29

Haplotypes that increase the risk for disease

Question 30

Protective Alleles

Answer 30

Haplotypes that decrease the risk for disease

Question 31

HLA B Haplotype Polymorphisms

Answer 31

Spondyloarthopathy

Question 32

HLA C Haplotype Poly morphisms

Answer 32

Psoriatic Arthritis