Multifactorial Genetics

Question 1

Multifactorial inheritance

Answer 1

• is shown by traits that are determined by a combination of multiple factors, genetic and usually environmental
• at least 71 loci associated with Crohn’s disease

Question 2

Multifactorial inheritance and quantitative traits

Answer 2

-quantitative or metric traits show continuous variation
-deals with traits and disease 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
-height and weight
-provides a framework for understanding genetic predisposition for disease
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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 (if there is a sex difference in susceptibility)
-male children of affected females
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Question 4

Common disorders with a genetic component

Answer 4

Cancers
Cleft lip
Coronary artery disease
Cleft palate
Diabetes
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 Epsilon

Answer 5

Loci that a variation at May contribute to Alzheimer’s but does not definitely mean you will get it. E3 and 2 are other variations, 4 is more likely

Question 6

Venous thrombosis

Answer 6

• at least two genetic factors in addition to environment
• factor v Leiden mutation (r596q) increases risk of VT 7 fold in heterozygotes and 80 fold in homozygotes
• prothrombin 20210G>A in 3’ untranslated region raises risk 4 fold
• oral contraceptive increases risk 22 fold
• OC with prothrombin increases risk 149 fold

Question 7

Digenic inheritance

Answer 7

• mixture of Mendelian and multifactorial inheritance
• only one mutation doesn’t cause disease but two do
• retinoids pigmentosa

Question 8

Age related macular degeneration

Answer 8

• allelic variation at 4 genes have an additive contribution to the risk of developing AMD
• 1% of the population homozygous at all three loci have >250 fold greater risk of AMD

Question 9

Normal distribution

Answer 9

14 loci–few with all resistant genes and few will all susceptible genes

Question 10

Height

Answer 10

Quantitative trait
54 loci in 2008
Average effect size of only 0.4 to 0.8 cm
Tallest 5% differ from shortest 5% by 26 cm
0.8 heritability

Question 11

Threshold model

Answer 11

Normal curve

Certain number of predisposing alleles are threshold for disease

Question 12

recurrence risk for parents of one affected child

Answer 12

cleft lip +/- cleft palate- 4-5%
cleft palate alone- 2-6%
cardiac defect (common type) 3-4%
pyloric stenosis 3%, 4% in males, 2.4% in females
hirschsprung 3-5%
clubfoot 2-8%
dislocation of hip 3-4%, 0.5% in males, 6.3% in females
neural tube defects 3-5%
scoliosis 10-15%

Question 13

mendelian vs multifactorial recurrence risk

Answer 13

• recurrence risk increases with each affected child

- mendelian remains 1/4, multifactorial goes from 1/25 to 1/12

Question 14

proportion of males to females

Answer 14

pyloric stenosis 5:1
clubfoot 2:1
cleft lip +/- palate 2:1
cleft palate alone 1:1.3
meningomyelocele 1:1.5
anencephaly 1:3
cong disloc hip 1:5.5

Question 15

pyloric stenosis

Answer 15

affects males more
sons of males 1/8
daughters of males 1/42
sons of females 1/5
daughters of females 1/14

Question 16

threshold effect and sex

Answer 16

• males more susceptible means they need fewer predisposing alleles to get sick
• females less susceptible means they have more alleles before they get sick and if they are sick they have high number
• therefore females pass on more alleles to sons who don’t take as much to become infected

Question 17

heritability

Answer 17

• proportion of 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 monozygotic and dizygotic twins
• see graph for examples- slope of line tells heritability

Question 18

heritability 2

Answer 18

• an estimate of the degree to which relatives will resemble each other
• difficult to determine in man, easiest to evaluate traits in twin studies
• indicated by concordance in traits in monozygotic twins vs dizigotic twins (equal environment assumption)
• incomplete concordance between identical (MZ) twins indicates non-genetic factors

Question 19

estimates of heritability of various disorders

Answer 19

schizophrenia- 85%
asthma 80%
cleft lip +/- palate 76
club foot 68
coronary artery disease 65
hypertension 62

Question 20

bayes theorem

Answer 20

1763
-assessing relative probability of two alternate possibilities
-considers likelihood that alternative hypotheses are true, given certain conditions
-set up columns with prior, conditional, posterior, and joint possibilities given that the hypothesis is true and in a separate column the alternatives then evaluate the relative probability at the end
DO EXAMPLES!!

Question 21

law of addition

Answer 21

-if two or more events are mutually exclusive, and the probability of event one occurring is p and the event two is q the probability of either is p+q

Question 22

law of multiplication

Answer 22

-if two or more events are independent and the probability of even one occurring is p and two is q, the probability of both is pxq