Complex inheritance

Question 1

What are multifactorial or complex disorders?

Answer 1

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

Question 2

What is the incidence and some examples of multifactorial disorders?

Answer 2

affect 2/3 of ppl! Congenital birth defects, MI, cancer< mental illness, diabetes, and Alzheimer disease

Question 3

Phenotypes of multifactorial disorders are divided into?

Answer 3

Qualitative and Quantitative

Question 4

What is a Qualitative phenotype?

Answer 4

Genetic disease that is either present/absent. It’s discrete or qualitative Ex. male/female

Question 5

What is Quantitative?

Answer 5

Measurable physiological or biochemical quantities. Ex: blood pressure, weight . . . continuous distribution, can’t say there is height or no height. NO discreteness-> measurable

Question 6

What is the primary feature of multifactorial or complex disorders?

Answer 6

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

Question 7

Concordant?

Answer 7

Two related individuals in a family have the same disease

Question 8

Discordant?

Answer 8

when only one family member of a pair of relatives is affected

Question 9

What can concordance in the presence of differing genotypes be explained by?

Answer 9

Genocopy and phenocopy

Question 10

Genocopy?

Answer 10

A genotype that determines a phenotype closely similar to that determined by a diff genotype.

Question 11

Phenocopy?

Answer 11

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.

Question 12

Measuring qualitative traits: How do you measure familial aggregation?

Answer 12

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

Question 13

Measuring qualitative traits:How is the relative contribution of genes and environment determined?

Answer 13

Concordance and allele sharing among relatives-most often used
Unrelated family member controls
Twin studies-expensive

Question 14

Measuring qualitative traits: Concordance and allele sharing among relatives

Answer 14

freq of disease concordance increases as the degree of relatedness increases

Question 15

Measuring qualitative traits:Unrelated family member controls

Answer 15

To separate family environment from genetic influence. Compare incidence of disease in unrelated family members(adoptees,spouses) with that in biological relatives.

Question 16

Measuring qualitative traits:Twin studies

Answer 16

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

Question 17

Measuring qualitative traits: Concordance of monozygotic twins vs dizygotic twins

Answer 17

Greater concordance in MZ than in DZ twins is strong evidence of a genetic component to the disease.
Twins reared apart

Question 18

What are some limitations of twin studies?

Answer 18

They don't have the exact same microenvironment. 
X-inactivation
Somatic DNA recombination
Diffs in environmental exposure
Fetal development
Volunteer-based ascertainment

Question 19

What is Analysis of Quantitative traits?

Answer 19

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.

Question 20

What is the Coefficient of Correlation (r)?

Answer 20

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

Question 21

What is heritability?

Answer 21

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.

Question 22

What does higher heritability mean?

Answer 22

the greater the genetic contribution of genetic differences among ppl causing variability of the trait.

Question 23

How do you estimate Heritability from twin studies?

Answer 23

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

Question 24

The difference in genotype can explain variance in phenotype in many single gene disorders. . . Give an example

Answer 24

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)

Question 25

What are some examples of multifactorial disorders?

Answer 25

``` Digenic Retinitis Pigmentosa. Venous thrombosis Hirschsprung disease Type 1 DM Alzheimer's disease Mental illness CAD ```

Question 26

What some multifactorial congenital malformations?

Answer 26

Neural tube defects Cleft lip Congenital heart defects

Question 27

What is Degenic Retinitis Pigmentosa?

Answer 27

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.

Question 28

What is Venous Thrombosis? Idiopathic cerebral VT?

Answer 28

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

Question 29

What is placental artery thrombosis?

Answer 29

Mutant allele of Factor V Variant in prothrombin(clotting factor) Allele for heat sensitive Methylene Tetrahydrofolate reductase

Question 30

What is deep vein thrombosis?

Answer 30

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

Question 31

What is Hirschsprung disease?

Answer 31

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

Question 32

What is Type 1 DM?

Answer 32

HLA-DR3 or HLA-DR4, other MHC haplotypes also. | Autoimmune process involving beta cell destruction

Question 33

What is Alzheimer Disease?

Answer 33

Fatal neurodegenerative disease. Familial agg and relative risk of complex inheritance. Role of epsilon4 allele of apoE

Question 34

Multifactorial congenital malformations: Anencephaly?

Answer 34

usually stillborn, the forebrain overlying meninges, vault of skull and skin are all absent.

Question 35

Multifactorial congenital malformations: Spina bifida?

Answer 35

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

Question 36

Multifactorial congenital malformations: Cleft lip and cleft palate?

Answer 36

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.

Question 37

What are congenital heart defects?

Answer 37

4-8/1000-common.Heterogeneous, multifactorial, lesions similar w/in families, 5 main groups. FLOW LESIONS MOST IMPORTANT AND MOST COMMON.

Question 38

What kind of lesions are seen in congenital heart defects?

Answer 38

Flow lesions.

Question 39

What is mental illness?

Answer 39

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.

Question 40

What is Coronary Heart Disease?

Answer 40

Mostly multifactorial with genetic/nongenetic predisposing factors, including HTN, obesity, DM, diet physical activity, and smoking

Question 41

Genetic counseling:Recurrence risk?

Answer 41

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.

Question 42

Genetic counseling:When does Empirical risk increase?

Answer 42

As the population prevalence increases.