Multifactorial Disorders Flashcards
What risk factors do multifactorial disorders have?
Genetic, environmental, and other risk factors
What are the risk factors for clubfoot?
Genetic - individuals with family history
Environmental - smoking elevates risk
Interaction of factors - smoking and family history together increase risk
What are quantitative genetics?
Study of quantitative traits which are traits that are measurable and usually resemble a bell curve or Gaussian distribution
How are multifactorial diseases quantitative traits?
Risk for multifactorial disease is a quantitative trait
Gaussian distribution of liability
Genetic and environmental contributions
What are quantitative traits determined by?
Quantitative trait loci (QTL)
QTL are polymorphic - more than one gene contributes to the phenotype
Alleles can be contributing or noncontributing
What does it mean if alleles are contributing or noncontributing?
Can increase the size of the goat or does not
How can alleles be contributing or noncontributing when it comes to the quantitative trait for multifactorial disease?
Quantitative trait is liability to disease
Alleles can raise or lower the risk for disease - susceptibility or protective alleles
Prevalence
Proportion of the population affected by the disease
Incidence
Number of new cases in given time divided by the size of the population
Recurrence risk
Probability of the event occurring again
What is the threshold of liability?
Means Individuals with above threshold risk will develop disorder during lifetime
Thresholds are different for men and women
Lower threshold means ______
High incidence of disease
What can affect the liability distribution?
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
How does the example of pyloric stenosis show concept of liability threshold?
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
What are important questions to consider in practice when contemplating risk?
How much of the risk is genetic (cannot be modified) and how much is environmental?
Best observed in twin studies to observe concordance
What is concordance?
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
What is compared in twin studies?
Compare concordances in pairs of monozygotic and dizygotic twins
What is compared in adoption studies?
Compare adopted children to their biological and adopted parents
What can be determined from twin studies?
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
How is heritability estimated?
H^2 = (Concordance MZ - Concordance DZ) * 2
What can be determined from adoption studies if you compare adopted children to their biological parents?
Compare adopted children to their biological parents - genetics is shared, environment is variable
High concordance means strong genetic component
What can be determined from adoption studies if you compare adopted children to their adoptive parents?
Compare adoptive children to their adoptive parents - environment is shared and genetics is variable
High concordance means strong environmental components
How is Type I diabetes evaluated from a traditional candidate gene approach?
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
How is Type I diabetes evaluated with genome-wide association study?
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
What are the design and outcomes of GWAS?
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
What did GWAS finds with type I diabetes?
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
What do we need to know about chromosomal region Chr VI?
Chromosomal region is inherited as a block (haplotype) - few or no crossovers at the locus
Very polymorphic locus, also called Major Histocompatibility Complex (MHC)
How does HLA Haplotypes function with Type I Diabetes?
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
How are HLA haplotypes inherited?
HLA haplotypes are inherited as a block
HLA haplotypes are codominant - both maternal and paternal copies expressed
What autoimmune disorder is associated with HLA-B haplotypes?
Spondyloarthropathy
What autoimmune disorder is associated with HLA-C haplotypes?
Psoriatic arthritis
How does relative risk (RR) and odds ratio (OR) describe the association for each allele?
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)
What does is it mean if the RR for an allele X is 1.5?
Means if we find that you are a carrier of alleles X, your risk is 1.5 times the risk of non-carrier
What is relative risk ratio?
A way to describe multifactorial diseases based on family history
Gamma = prevalence of disease in relative “r” of affected person / prevalence in general population
What is the characteristic inheritance of multifactorial diseases? x4
- Multifactorial diseases do not follow a clear Mendelian pattern of inheritance
- Show familial aggregation
- Frequently show incomplete penetrance
- Disease is much more common among close relatives of the proband than it is among less closely related persons
How is recurrence risk different for multifactorial disorders and Mendelian disorders?
Recurrence risk is low compared to single gene disorders
