Complex inheritance Flashcards
What are multifactorial or complex disorders?
Run in families but do not conform to mendelian inheritance pattern. Diseases that result from the complex interactions b/w a number of genetic and environmental factors.
Gene-gene interactions (polygenic/multigenic effects) and gene-environment interactions
What is the incidence and some examples of multifactorial disorders?
affect 2/3 of ppl! Congenital birth defects, MI, cancer< mental illness, diabetes, and Alzheimer disease
Phenotypes of multifactorial disorders are divided into?
Qualitative and Quantitative
What is a Qualitative phenotype?
Genetic disease that is either present/absent. It’s discrete or qualitative Ex. male/female
What is Quantitative?
Measurable physiological or biochemical quantities. Ex: blood pressure, weight . . . continuous distribution, can’t say there is height or no height. NO discreteness-> measurable
What is the primary feature of multifactorial or complex disorders?
Familial aggregation-affected individuals may cluster in families. Families share genes and environments.
May not be totally due to genetic contribution
May be due to chance/sharing environmental factors
Concordant?
Two related individuals in a family have the same disease
Discordant?
when only one family member of a pair of relatives is affected
What can concordance in the presence of differing genotypes be explained by?
Genocopy and phenocopy
Genocopy?
A genotype that determines a phenotype closely similar to that determined by a diff genotype.
Phenocopy?
A mimic of a phenotype that is usually determined by a specific genotype, produced instead by interaction of some environmental factor with a normal genotype.
Measuring qualitative traits: How do you measure familial aggregation?
Relative risk=ratio of frequency of disease in relatives of affected pro band to frequency in general population.=> larger relative risk, the greater the familial aggregation
Case control studies=patients with disease are compared to individuals without the disease. Freq of disease in extended families of cases is compared with freq of positive family history among controls. Subject to bias. Association does not prove causation
Measuring qualitative traits:How is the relative contribution of genes and environment determined?
Concordance and allele sharing among relatives-most often used
Unrelated family member controls
Twin studies-expensive
Measuring qualitative traits: Concordance and allele sharing among relatives
freq of disease concordance increases as the degree of relatedness increases
Measuring qualitative traits:Unrelated family member controls
To separate family environment from genetic influence. Compare incidence of disease in unrelated family members(adoptees,spouses) with that in biological relatives.
Measuring qualitative traits:Twin studies
Concordance in monozygotic twins-less than 100% is strong evidence that non genetic factors play a role in the disease. If 100% concordance, then genes are the factor
Measuring qualitative traits: Concordance of monozygotic twins vs dizygotic twins
Greater concordance in MZ than in DZ twins is strong evidence of a genetic component to the disease.
Twins reared apart
What are some limitations of twin studies?
They don't have the exact same microenvironment. X-inactivation Somatic DNA recombination Diffs in environmental exposure Fetal development Volunteer-based ascertainment
What is Analysis of Quantitative traits?
Any physiological qty that can be measured is a quantitative phenotype, with a mean and a variance. NORMAL (GAUSSIAN) DISTRIBUTION-mean/median/mode all coincide at the same point.
The variance/SD of a measured qty in the population is called the total phenotypic variance.
What is the Coefficient of Correlation (r)?
A statistical measure applied to a pair of measurements.R ranges from 0 to +1 with R=0 means no correlation, +1 means positive correlation, and -1 means negative correlation
What is heritability?
Fraction of the total phenotypic variance of quantitative trait that is caused by genes. Measure of the extent to which different alleles at various loci are responsible for the variability in a given quantitative trait seen across a population.
What does higher heritability mean?
the greater the genetic contribution of genetic differences among ppl causing variability of the trait.
How do you estimate Heritability from twin studies?
H^2=0, no genetic contribution
h^2=1, genes are responsible.
H^2=(variance in DZ pairs-variance in MZ pairs)/variance in DZ pairs
The difference in genotype can explain variance in phenotype in many single gene disorders. . . Give an example
Cystic fibrosis: likelihood of pancreatic insufficiency.
Variation in degree of pulmonary disease: maybe due to effect of MBL2 and TGFB1.
MBL2 is mannose binding lectin that aids in phagocytosis and complement activation.
TGFB1 increases TGFB levels promoting scarring and fibrosis after inflammation (TNFs)
What are some examples of multifactorial disorders?
Digenic Retinitis Pigmentosa. Venous thrombosis Hirschsprung disease Type 1 DM Alzheimer's disease Mental illness CAD
What some multifactorial congenital malformations?
Neural tube defects
Cleft lip
Congenital heart defects
What is Degenic Retinitis Pigmentosa?
Form of retinal degeneration. 2 rare mutations in 2 diff unlinked genes that encode for proteins PERIPHERIN AND ROM1 found in photoreceptor.Heterozygotes for both Rom! adn peripherin photoreceptor membrane proteins develop the disease.
What is Venous Thrombosis? Idiopathic cerebral VT?
Clot formation in cerebral veins in absence of infection or tumor. Requires 2 mutant alleles and an environmental influence.
Risks:Mutant allele of Factor V
Variant of prothrombin (clotting factor)
Use of OCPs
What is placental artery thrombosis?
Mutant allele of Factor V
Variant in prothrombin(clotting factor)
Allele for heat sensitive Methylene Tetrahydrofolate reductase
What is deep vein thrombosis?
Mutant allele of Factor V
Variant of prothrombin (clotting factor)
Environmental factors like trauma, surgery, malignant disease, prolonged immobilization, OCP, advanced age. . . Exercise care w/ OCP prescriptions
What is Hirschsprung disease?
complete absence of some or all of the intrinsic ganglion cells in the colon, resulting in severe constipation, symptoms of intestinal obstruction, and massive dilation of the colon.
Mutation in Ret (Tyrosine kinase receptor), ligand gdnf, endothelin B receptor and its ligand endothelin. May involve mutations in many genes
What is Type 1 DM?
HLA-DR3 or HLA-DR4, other MHC haplotypes also.
Autoimmune process involving beta cell destruction
What is Alzheimer Disease?
Fatal neurodegenerative disease. Familial agg and relative risk of complex inheritance. Role of epsilon4 allele of apoE
Multifactorial congenital malformations: Anencephaly?
usually stillborn, the forebrain overlying meninges, vault of skull and skin are all absent.
Multifactorial congenital malformations: Spina bifida?
failure of fusion of the arches of the vertebrae. Varying degrees of severity. Freq appears to vary with social factors and season of birth, and oscillates widely overtime.*Maternal folic acid deficiency
Multifactorial congenital malformations: Cleft lip and cleft palate?
Maternal smoking is a RISK! Failure of fusion of frontal process with maxillary process at 35th day of gestation. Sporadic form displays familial agg. Possible genes involved are transcription factor(TF) genes TBX1,MSX1, IRF6, and FGFR1.
What are congenital heart defects?
4-8/1000-common.Heterogeneous, multifactorial, lesions similar w/in families, 5 main groups. FLOW LESIONS MOST IMPORTANT AND MOST COMMON.
What kind of lesions are seen in congenital heart defects?
Flow lesions.
What is mental illness?
Affects 4% of human population worldwide, schizophrenia and bipolar disease are most severe forms. Considerable evidence of genetic contribution-genes largely unknown except high prevalence in carriers of 22q11 deletion-velocardial syndrome.
What is Coronary Heart Disease?
Mostly multifactorial with genetic/nongenetic predisposing factors, including HTN, obesity, DM, diet physical activity, and smoking
Genetic counseling:Recurrence risk?
increases as # of affected relatives increases.
Increases if affected individ has severe expression of disease.
Higher if the affected imdivid is a member of the less commonly affected sex
Decreases rapidly for more remotely related relatives.
Genetic counseling:When does Empirical risk increase?
As the population prevalence increases.
