Multifactorial Disorders

Question 1

What risk factors do multifactorial disorders have?

Answer 1

Genetic, environmental, and other risk factors

Question 2

What are the risk factors for clubfoot?

Answer 2

Genetic - individuals with family history

Environmental - smoking elevates risk

Interaction of factors - smoking and family history together increase risk

Question 3

What are quantitative genetics?

Answer 3

Study of quantitative traits which are traits that are measurable and usually resemble a bell curve or Gaussian distribution

Question 4

How are multifactorial diseases quantitative traits?

Answer 4

Risk for multifactorial disease is a quantitative trait

Gaussian distribution of liability

Genetic and environmental contributions

Question 5

What are quantitative traits determined by?

Answer 5

Quantitative trait loci (QTL)

QTL are polymorphic - more than one gene contributes to the phenotype

Alleles can be contributing or noncontributing

Question 6

What does it mean if alleles are contributing or noncontributing?

Answer 6

Can increase the size of the goat or does not

Question 7

How can alleles be contributing or noncontributing when it comes to the quantitative trait for multifactorial disease?

Answer 7

Quantitative trait is liability to disease

Alleles can raise or lower the risk for disease - susceptibility or protective alleles

Question 8

Prevalence

Answer 8

Proportion of the population affected by the disease

Question 9

Incidence

Answer 9

Number of new cases in given time divided by the size of the population

Question 10

Recurrence risk

Answer 10

Probability of the event occurring again

Question 11

What is the threshold of liability?

Answer 11

Means Individuals with above threshold risk will develop disorder during lifetime

Thresholds are different for men and women

Question 12

Lower threshold means ______

Answer 12

High incidence of disease

Question 13

What can affect the liability distribution?

Answer 13

Liability distribution is different for different populations - population of individuals with affected relative have higher risk than general population

Family history of disorder allows placing patient in appropriate population

Sex of expected child allows determination of appropriate threshold

Question 14

How does the example of pyloric stenosis show concept of liability threshold?

Answer 14

Pyloric stenosis affects more boys than girls so threshold of liability for males is lower

An affected female has inherited more contributing alleles than an affected boy

Recurrence risk is higher for families with affected female - more contributing alleles in these families

Question 15

What are important questions to consider in practice when contemplating risk?

Answer 15

How much of the risk is genetic (cannot be modified) and how much is environmental?

Best observed in twin studies to observe concordance

Question 16

What is concordance?

Answer 16

Can be observed in pairs of subjects like sibling pairs, twins, parent/child pairs

Refers to how often a traits occurs in both members of the pair

Question 17

What is compared in twin studies?

Answer 17

Compare concordances in pairs of monozygotic and dizygotic twins

Question 18

What is compared in adoption studies?

Answer 18

Compare adopted children to their biological and adopted parents

Question 19

What can be determined from twin studies?

Answer 19

Both monozygotic twins and dizygotic twins grow up under similar circumstances - environmental is constant and genetics is variable

If concordance in MZ is higher than in DZ, trait has genetic component

Question 20

How is heritability estimated?

Answer 20

H^2 = (Concordance MZ - Concordance DZ) * 2

Question 21

What can be determined from adoption studies if you compare adopted children to their biological parents?

Answer 21

Compare adopted children to their biological parents - genetics is shared, environment is variable

High concordance means strong genetic component

Question 22

What can be determined from adoption studies if you compare adopted children to their adoptive parents?

Answer 22

Compare adoptive children to their adoptive parents - environment is shared and genetics is variable

High concordance means strong environmental components

Question 23

How is Type I diabetes evaluated from a traditional candidate gene approach?

Answer 23

Type I diabetes is an autoimmune disease

Look for polymorphisms in genes involved in specificity of immune response

Calculate by how much the polymorphism elevates the risk

Question 24

How is Type I diabetes evaluated with genome-wide association study?

Answer 24

Make no assumptions

Find SNPs that associate with Type I Diabetes (often inherited together)

Calculate how much more likely it is that the association is nor random

Question 25

What are the design and outcomes of GWAS?

Answer 25

GWAS = Genome wide association study

Analyze whole genome for SNP markers in affected families - SNP serves as genetic marker and SNP is a landmark on a chromosomes, not the variation that contributes to risk

Compare SNP in affected and unaffected individuals - look for SNP markers that occur more often in individuals with disease

Calculate odds that the association is real or by chance

Question 26

What did GWAS finds with type I diabetes?

Answer 26

Found strong linkage of locus on Chromosome 6p with type I diabetes

Locus on chromosome 6p - coding for human leukocyte antigen (HLA) genes coding for antigen presenting proteins

Question 27

What do we need to know about chromosomal region Chr VI?

Answer 27

Chromosomal region is inherited as a block (haplotype) - few or no crossovers at the locus

Very polymorphic locus, also called Major Histocompatibility Complex (MHC)

Question 28

How does HLA Haplotypes function with Type I Diabetes?

Answer 28

HLA proteins mediate antigen presentation to T cells

Strong correlation of HLA haplotype variants with type I diabetes - some variants increase risk (susceptibility alleles) and other variants decrease the risk (protective alleles)

Type I is an autoimmune disorder and HLA genes are determinants of immune specificity

Question 29

How are HLA haplotypes inherited?

Answer 29

HLA haplotypes are inherited as a block

HLA haplotypes are codominant - both maternal and paternal copies expressed

Question 30

What autoimmune disorder is associated with HLA-B haplotypes?

Answer 30

Spondyloarthropathy

Question 31

What autoimmune disorder is associated with HLA-C haplotypes?

Answer 31

Psoriatic arthritis

Question 32

How does relative risk (RR) and odds ratio (OR) describe the association for each allele?

Answer 32

Describes how much more likely is the carrier of the allele to develop the disease than the non-carrier

Ratio less than 1 means that the alleles is protective (lowers risk of carrier)

Question 33

What does is it mean if the RR for an allele X is 1.5?

Answer 33

Means if we find that you are a carrier of alleles X, your risk is 1.5 times the risk of non-carrier

Question 34

What is relative risk ratio?

Answer 34

A way to describe multifactorial diseases based on family history

Gamma = prevalence of disease in relative “r” of affected person / prevalence in general population

Question 35

What is the characteristic inheritance of multifactorial diseases? x4

Answer 35

1. Multifactorial diseases do not follow a clear Mendelian pattern of inheritance
2. Show familial aggregation
3. Frequently show incomplete penetrance
4. Disease is much more common among close relatives of the proband than it is among less closely related persons

Question 36

How is recurrence risk different for multifactorial disorders and Mendelian disorders?

Answer 36

Recurrence risk is low compared to single gene disorders