Exam #5: Multifactorial Disorders Flashcards
How do you estimate the number of genes involved in the inheritance of a quantitative trait?
- 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
How does a multifactorial pedigree differ from an autosomal dominant pedigree?
- Pedigrees of families with multifactorial disease do not show easily recognizable patterns
- Most closely resemble autosomal dominant with incomplete penetrance
Why does the recurrence risk for a multifactorial disease change every time a relative is diagnosed with the disorder?
- 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
What are the gender-specific differences in recurrence risk for multifactorial disorders such as pyloric stenosis?
- 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
How are the genetic & environmental influences on complex diseases estimated?
- Twin studies & adoption studies
How do you map multiple contributing alleles?
- 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
What are the statistical measures that describe the risk for multifactorial diseases in general populations?
- Disease association= quantifies how the allele in question influences the risk of the disorder
Relative risk ratio
Prevalence of the disease in relative “r” of affected person/ prevalence in general populaiton
HLA Haplotypes & DM-I
- 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
What are the most common genetic diseases?
1) Multifactorial
2) Single gene
3) Chromosomal
Multifactoral Disease
Combination of polymorphic alleles that are not ideal for the current environment
Quantitative Traits
Traits that can be measured such as height
What is the likelihood that offspring will inherit a multifactorial disease if there are many genes involved? What if there are few genes?
- Low if many genes b/c there will be a lower fraction of extreme phenotypes
- Higher if few genes
What is the bell curve of phenotype distribution in a population called in a multifactorial disease?
Liability Distribution, where disease results if the threshold of liability is crossed
Pyloric Stenosis
- Area between the stomach & duodenum is narrowed
- Causes frequent vomiting & constipation
Monozygotic twins
100% genetically identical (single fertilized egg)
Dizygotic twins
50% genetically identical (simultaneous fertilization of two eggs by two sperm)
Concordance Rate
How often a trait is shared by both individuals in a pair
Heritability
- (Concordance MZ- Concordance DZ) x2
- High heritability indicates a strong genetic component
- Values should be between 0-1 (if not, must be other factors)
Incidence
How many new cases are recorded in a given time, divided by the size of the population
Prevalence
Proportion of the population that is affected by the disease at any given time
What is the risk of developing a common birth defect in the general population?
0.5%
What is the risk of developing a common birth defect if a second degree relative is affected?
- 0.7-2%
- 2-4x higher
What is the risk of developing a common birth defect if a first degree relative is affected?
- 3-4%
- 6-8x higher
What is the risk of developing a common birth defect if two first degree relatives are affected?
- 5-8%
- 10-16x higher
What is the risk of developing a common birth defect if three first degree relatives are affected?
- 9-12%
- 18-24x higher
What is the risk of developing a common birth defect if an identical twin is affected?
- 20-30%
- 40-60x higher
What are the four characteristics of multifactorial diseases that set them apart from single-gene disorders?
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
Susceptibility Alleles
Haplotypes that increase the risk for disease
Protective Alleles
Haplotypes that decrease the risk for disease
HLA B Haplotype Polymorphisms
Spondyloarthopathy
HLA C Haplotype Poly morphisms
Psoriatic Arthritis
