Multifactorial Disorders Flashcards
How much of the population do disorders with multifactorial inheritance affect?
60% (most common – chromosomal/genomic disorders only affect 0.38%, single gene only affect 2%)
Quantitative traits
Traits such as height that are able to be measured that are normally determined by many genes
Contributing allele
Contributes to the trait (ex. increases height)
Noncontributing allele
Does not contribute to the trait (ex. does not affect height)
How can one estimate the number of genes involved in the inheritance of quantitative trait?
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
Prevalence vs. incidence
Prevalence is the proportion of the population affected, while incidence is the number of new cases divided by the size of the population
Liability distribution
Bell curve of a phenotype distribution in a population of multifactorial diseases
Threshold of liability
Crossing this results in disease; different for males and females and influenced by environmental factors
How do the pedigrees for multifactorial inheritance and autosomal dominant inheritance differ?
Multifactorial inheritance patterns do not follow Mendelian rules; show familial aggregation, incomplete penetrance, and are more common among close relatives
Recurrence risk
Chance of another child getting a certain disease; for multifactorial disorders, it is higher than the occurrence risk
Why does the recurrence risk for multifactorial diseases change every time a relative is diagnosed with the disorder?
Each birth of an affected child changes the risk analysis because it means that between parents there are enough contributing alleles to cause disease
Pyloric stenosis
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
Gender-specific differences in recurrence risk for multifactorial disorders (ex. pyloric stenosis)
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
Concordance rate
The rate at which twins share a trait
Twin studies
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
Heritability
Estimate of how much of observed phenotypic variation is due to genetic factors, calculated by (concordance MZ – concordance DZ) * 2; theoretically cannot exceed 1
Prevalence figures for common birth defects
See p. 604 – autism, idiopathic epilepsy, and mental retardation are highly heritable, followed closely by diabetes and then BMI
Adoption studies
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
Affected sibling pairs
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
Model-free linkage analysis
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
Mapping of multiple contributing alleles
Can be done by linkage analysis (though imprecise)
Statistical measures describing the risk for multifactorial diseases in general populations
- -Incidence and prevalence
- -Risk prediction based on family history
- -Risk of spontaneous development due to multifactorial inheritance
Empirical risks
Information from epidemiological studies for genetic counseling that uses prevalence and incidence to describe complex diseases
Relative risk ratio λr
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
Risks of multifactorial birth defects
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%
Relative risk (RR)
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
Disease association of certain allele
Statistical measure quantifying how allele in question influences risk of disorder by calculating RR
How does a family history or patient’s genotype influence the prediction of risk?
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
Type I diabetes
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)
Major histocompatibility complex (MHC)
Locus found on chromosome 6 containing multiple genes that encode surface cell proteins for immune response
Human leukocyte antigens (HLA) haplotypes
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
Codominant manner of expression
How HLA haplotypes are expressed; each parent has 2 haplotypes and expresses them both, and each parent passes on one haplotype
Role of HLA haplotypes in development of type I diabetes and other autoimmune disorders
Certain HLA haplotypes favor these disorders (susceptibility alleles = increase risk for T1D) while some decrease risk for T1D (protective alleles)
HLA haplotype disorders
HLA-B = spondyloarthropathy HLA-C = psoriatic arthritis
