Multifactorial Disorders

Question 1

How much of the population do disorders with multifactorial inheritance affect?

Answer 1

60% (most common – chromosomal/genomic disorders only affect 0.38%, single gene only affect 2%)

Question 2

Quantitative traits

Answer 2

Traits such as height that are able to be measured that are normally determined by many genes

Question 3

Contributing allele

Answer 3

Contributes to the trait (ex. increases height)

Question 4

Noncontributing allele

Answer 4

Does not contribute to the trait (ex. does not affect height)

Question 5

How can one estimate the number of genes involved in the inheritance of quantitative trait?

Answer 5

Look at the shape of a phenotype distribution curve – the more genes involved, the lower the probability of an offspring inheriting all or none of the contributing alleles and the lower the fraction of extreme phenotypes

Question 6

Prevalence vs. incidence

Answer 6

Prevalence is the proportion of the population affected, while incidence is the number of new cases divided by the size of the population

Question 7

Liability distribution

Answer 7

Bell curve of a phenotype distribution in a population of multifactorial diseases

Question 8

Threshold of liability

Answer 8

Crossing this results in disease; different for males and females and influenced by environmental factors

Question 9

How do the pedigrees for multifactorial inheritance and autosomal dominant inheritance differ?

Answer 9

Multifactorial inheritance patterns do not follow Mendelian rules; show familial aggregation, incomplete penetrance, and are more common among close relatives

Question 10

Recurrence risk

Answer 10

Chance of another child getting a certain disease; for multifactorial disorders, it is higher than the occurrence risk

Question 11

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

Answer 11

Each birth of an affected child changes the risk analysis because it means that between parents there are enough contributing alleles to cause disease

Question 12

Pyloric stenosis

Answer 12

Area between stomach and duodenum is narrowed, resulting in frequent episodes of vomiting and constipation (1/200 males, 1/1000 females) – low threshold for males, high for females

Question 13

Gender-specific differences in recurrence risk for multifactorial disorders (ex. pyloric stenosis)

Answer 13

Pyloric stenosis is more common in males, so if a female is born with this problem then the risk increases even more – means there are enough contributing alleles to cross higher threshold of liability

Question 14

Concordance rate

Answer 14

The rate at which twins share a trait

Question 15

Twin studies

Answer 15

Compare similar genetic makeup for concordance rate – diseases with significant genetic component show higher concordance rate in monozygotic twins

• -Monozygotic twins (MZ) come from single fertilized egg
• -Dizygotic twins (DZ) come from simultaneous fertilization of two eggs

Question 16

Heritability

Answer 16

Estimate of how much of observed phenotypic variation is due to genetic factors, calculated by (concordance MZ – concordance DZ) * 2; theoretically cannot exceed 1

Question 17

Prevalence figures for common birth defects

Answer 17

See p. 604 – autism, idiopathic epilepsy, and mental retardation are highly heritable, followed closely by diabetes and then BMI

Question 18

Adoption studies

Answer 18

Can determine whether a disease is caused more by genetic or environmental factors by seeing whether adopted child develops same disease as biological parents/siblings or adopted parents/siblings

Question 19

Affected sibling pairs

Answer 19

Genome is analyzed for presence of shared polymorphic SNP markers in linkage analysis – loci shared by affected siblings more than expected are probably involved in the disease

Question 20

Model-free linkage analysis

Answer 20

Mapping unknown number of contributing loci based on assumptions that relatives affected by the same disorder will have disease-causing alleles in common; insensitive due to need of large sample size

Question 21

Mapping of multiple contributing alleles

Answer 21

Can be done by linkage analysis (though imprecise)

Question 22

Statistical measures describing the risk for multifactorial diseases in general populations

Answer 22

• -Incidence and prevalence
• -Risk prediction based on family history
• -Risk of spontaneous development due to multifactorial inheritance

Question 23

Empirical risks

Answer 23

Information from epidemiological studies for genetic counseling that uses prevalence and incidence to describe complex diseases

Question 24

Relative risk ratio λr

Answer 24

Way to describe multifactorial diseases by dividing prevalence of disease in relative “r” of affected person by prevalence in general population – incidence and prevalence differ in people with affected relatives

Question 25

Risks of multifactorial birth defects

Answer 25

General population: 0.5%
2nd-degree affected relative: 0.7-2%
1st-degree relative: 3-4%
Two 1st-degree relatives: 5-8%
Identical twin: 20-30%

Question 26

Relative risk (RR)

Answer 26

Used to describe disease association of an allele (possibility of developing a disorder) – done with (a/(a+b))/(c/(c+d)) to compare percentage of people with allele who develop the trait with percentage of people who develop it WITHOUT the allele

Question 27

Disease association of certain allele

Answer 27

Statistical measure quantifying how allele in question influences risk of disorder by calculating RR

Question 28

How does a family history or patient’s genotype influence the prediction of risk?

Answer 28

Relative risk ratio (λr) is used to determine how likely you are to develop the disease based on your family history, and relative risk (RR) is used to determine how likely you are to develop the disease based on the allele you are carrying

Question 29

Type I diabetes

Answer 29

Prevalence: 1/200
Results from autoimmune destruction of β cells of pancreatic islets
Concordance rate in MZ twins = 40% (not due to just genetics)
λs = 12 (of sibling)

Question 30

Major histocompatibility complex (MHC)

Answer 30

Locus found on chromosome 6 containing multiple genes that encode surface cell proteins for immune response

Question 31

Human leukocyte antigens (HLA) haplotypes

Answer 31

Polymorphic gene blocks that have dozens of allelic variants with very little recombination in MHC region; haplotypes are associated with autoimmune disorders – must be matched for organ transplants – linkage disequilibrium

Question 32

Codominant manner of expression

Answer 32

How HLA haplotypes are expressed; each parent has 2 haplotypes and expresses them both, and each parent passes on one haplotype

Question 33

Role of HLA haplotypes in development of type I diabetes and other autoimmune disorders

Answer 33

Certain HLA haplotypes favor these disorders (susceptibility alleles = increase risk for T1D) while some decrease risk for T1D (protective alleles)

Question 34

HLA haplotype disorders

Answer 34

HLA-B = spondyloarthropathy
HLA-C = psoriatic arthritis