Multifactorial inheritance
- 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
Multifactorial inheritance and quantitative traits
-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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Multifactorial traits: mode of inheritance
-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
‘HthjvF-song
Common disorders with a genetic component
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
APOE Epsilon
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
Venous thrombosis
- 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
Digenic inheritance
- mixture of Mendelian and multifactorial inheritance
- only one mutation doesn’t cause disease but two do
- retinoids pigmentosa
Age related macular degeneration
- 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
Normal distribution
14 loci–few with all resistant genes and few will all susceptible genes
Height
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
Threshold model
Normal curve
Certain number of predisposing alleles are threshold for disease
recurrence risk for parents of one affected child
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%
mendelian vs multifactorial recurrence risk
- recurrence risk increases with each affected child
- mendelian remains 1/4, multifactorial goes from 1/25 to 1/12
proportion of males to females
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
pyloric stenosis
affects males more sons of males 1/8 daughters of males 1/42 sons of females 1/5 daughters of females 1/14
threshold effect and sex
- 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
heritability
- 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
heritability 2
- 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
estimates of heritability of various disorders
schizophrenia- 85% asthma 80% cleft lip +/- palate 76 club foot 68 coronary artery disease 65 hypertension 62
bayes theorem
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!!
law of addition
-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
law of multiplication
-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
