Unit II- Quantitative Genetics, Heritability and Bayesian Calculations

Question 1

Multifactorial inheritance

Answer 1

-is shown by traits that are determined by a combination of multiple factors, genetic and usually also environmental

Question 2

Multifactorail Inheritance and Quantitative Traits

Answer 2

• quantitative or metric traits show continuous variation
• deals with traits and diseases that are not inherited in a simple Mendelian fashion nor associated with chromosomal abnormalities, but in which there is considerable evidence that genetic factors play an important role in their causation
• provides a framework for understanding genetic predisposition to disease

Question 3

Multifactorial traits: mode of inheritance

Answer 3

• familial clustering but without obvious family pattern
• the recurrence risk is higher the more family members that are affected
• the recurrence risk is higher the more severe the malformation
• the recurrence risk is greatest in the most susceptible sex offspring of the least susceptible affected parent

Question 4

Common disorders with a genetic component

Answer 4

• cancers (5% are familial)
• cleft lip
• coronary artery disease
• cleft palate
• diabetes mellitus
• epilepsy
• hypertension
• manic- depressive disorders
• neural tube defects
• schizophrenia
• ~30% of pediatric and 10% of adult US hospital admissions have a significant genetic component

Question 5

APOE gene and Alzheimers disease

Answer 5

• variation at the APOE eplsilion4 allele
• the greater the number of epsilon4 alleles the greater the change of developing AD
• this is one genetic factor and there are other genetic and environmental factors

Question 6

Venous thrombosis

Answer 6

• Factor V Leiden mutation (R506Q) increases risk of VT 7 fold in heterozygotes and 80 fold in homozygotes
• Prothrombin (F2) 20210G>A in 3’ untranslated region raises venous thrombosis risk about 4 fold
• use of oral contraceptives (environment) increases risk of thrombosis 22 fold
• using oral contraceptives and being a factor V leiden heterozygote increases risk modestly compared to each alone. However if a woman uses oral contraceptives and is heterozygotes for the prothrombin 20210G>A mutation her risk rises to 149 fold

Question 7

Digenic Inheritance

Answer 7

-two different genes
-retinitis pigmentosa
peripherin locus and ROM1 locus

Question 8

Gaussian (Normal) DIstribution

Answer 8

–the average had 7 if there are 14 loci

Question 9

Height example

Answer 9

• heritability of 0.8
• as of 2008, 54 loci affecting height have been identified
• average effect size of only 0.4 to 0.8 cm
• tallest 5% differ from the short 5% by 26cm

Question 10

Threshold model

Answer 10

• more than 9 predisposing alleles is enough to cross threshold
• individuals with less than 9 predisposing alleles are usually not affective

Question 11

Recurrence risk of normal parens of one affected child

Answer 11

Cleft lip +/- Cleft palate 5%
cleft palate alone 2-6%
Cardiac defect 3-4%
Pyloric stenosis 3%
Hirschsprung anomaly 3-5%
Clubfoot 2-8%
Dislocation of hip 3-4%
Neural tube defects 3-5%
Scoliosis 1015%

*none as high as the 25% expected from an autosomal recessive or 50% from an autosomal dominant

Question 12

More children and recurrance risk

Answer 12

in multifactorial disorders, the estimate of the reccurance rate goes up with the birth of each affected child
-risk stays at 1/4 for each independent pregnancy

Question 13

Multifactorial disease and sexes

Answer 13

• in some multifactorial disorderrs the disease has different frequencies in the different sexes
• in those disorders the most most likely individual to be affected is the most susceptible sex offspring of the least susceptible sex parent
• threshold maybe different in different sexes

Question 14

Heritability

Answer 14

• is the proportion of the phenotypic variance caused by additive genetic variance
• is reflected by the degree of resemblance between relatives
• is a correlation coefficient which can be calculated using Normal distribution statistics
• can be estimated from the concordance rates in monozygyotic and dizygotic twins

Question 15

Regression to the mean

Answer 15

• children of tall parents, although still taller than average tend to be shorter than their parents
• children of short parents although shorter than average tend to be taller than their parents

Question 16

Heritability continued

Answer 16

• is an estimate of the degree to which relatives will resemble one another
• is difficult to determine in man, easiest to evaluate traits in twin studies
• is indicated by concordance in traits in monozygotic twins versus dizygotic twins (equal environment assumption)
• incomplete concordance between indentical MZ twins indicates non-genetic factors

Question 17

Heritability of various disorders

Answer 17

Schizophrenia- 85
Asthma- 80
Cleft lip +/- 76
Club foot -76
Coronary artery disease 65
Hypertension 62

Question 18

Bayes Theorem

Answer 18

method of assessing the relative probabilty of two alternative possibilities

• considers the likelihood that alternative hypothesis are true, given certain conditions
• set up columns with prior, conditional joint and posterior possibilities given that the hypothesis is true and in a separate column the alternatives, then evaluate the relative probability at the end

Question 19

Bayesian

Answer 19

X is carrier X is not a carrier
prior A 1-A =B
conditional C D
Joint AC BD (usually 1)
posterior AC/AC + BD

Question 20

DMD Bayesian

Answer 20

-example when D is not 1