Multifactorial Inheritance

Question 1

Multifactorial inheritance

Answer 1

Polygenic- many genes contribute to a trait, true for most quantitative traits, may show a normal distribution

Question 2

Threshold model

Answer 2

Some diseases are only present or absent, distribution in population is not that of single genes

Question 3

Liability distribution

Answer 3

Individuals at one end of the curve are affected

Question 4

Threshold of liability

Answer 4

Limit separates normal from affected, may differ by sex or other factor

Question 5

Recurrence risk

Answer 5

Complex, unknown number of genes, degree to which each gene and allele contributes, genetic constitution of parents unknown, environmental influence varies, empirical risks are derived

Question 6

Specific indications

Answer 6

Relative recurrence risks- higher if more than one affected family member, higher if proband is more severely affected, higher if proband is of less affected sex, decreases rapidly with more distant relationship, risk to siblings and offspring is sqrt of population risk

Question 7

Locus heterogeneity

Answer 7

Mutations in different genes give similar phenotype, different families have different mutations, in any one family a single mutation in a single gene

Question 8

Background effects on major genes

Answer 8

One gene accounts for significant variation, influenced by environment or modifier genes, overall effect is continuous distribution

Question 9

Twin studies

Answer 9

Compare monozygotic (100%) to dizygotic twins (50%), determine relative recurrence rate of trait

Question 10

Concordant

Answer 10

Both twins are affected

Question 11

Discordant

Answer 11

One twin affected, one is not

Question 12

Concordance rate

Answer 12

For qualitative traits

Question 13

Intraclass correlation

Answer 13

For quantitative traits

Question 14

Measuring heritability

Answer 14

Heritability is the difference between monozygotic and dizygotic twin concordance rate, proportion of variance of a trait that is determined by genes, measured from 0 to 1

Question 15

Adoption studies

Answer 15

Compare inheritance of trait in adopted vs. natural children, compare adopted children from affected parents vs. adopted children of unaffected parents

Question 16

Finding genes

Answer 16

More complex than single-gene traits, may be multiple causes- specific genes, phenocopies, look for quantitative trait loci (QTLs)

Question 17

Phenocopies

Answer 17

Have trait but not with genetic cause, possibly environmental

Question 18

Finding quantitative trait loci (QTLs)

Answer 18

Population with affected and unaffected members, perform genome scan, genetic constitution at many loci scattered throughout the genome, compare alleles at each locus with trait, locate regions which correlate with trait

Question 19

Affected sib-pair method

Answer 19

Two siblings affected with the same disorder, share ~50% of genes, must share genes causing effect, use pairs from many families, compare to each other and unaffected siblings, find regions in common

Question 20

Common multifactorial disorders

Answer 20

Identifying major genes aids in risk estimates, health problems to consider- heart disease, hypertension, diabetes

Question 21

Heart disease

Answer 21

Mainly coronary artery disease (CAD), narrowed by atherosclerosis, fatty deposits, impedes blood flow, can lead to myocardial infarction or stroke, risk factors- obesity, cigarettes, hypertension, high cholesterol

Question 22

Family history

Answer 22

Positive family history increases risk 2-7 fold, greater risk with more affected relatives, affected relative is female, early age of onset for affected relative

Question 23

Familial hypercholesterolemia (FH)

Answer 23

Quantitative trait with a major gene, autosomal dominant inheritance, doubles serum cholesterol, accelerates atherosclerosis, produces xanthomas (fatty deposits), higher risk of coronary artery disease and MI, homozygotes more severely affected

Question 24

LDL receptor

Answer 24

LDL in blood binds to LDLR, glycoprotein made in RER, pass through Golgi, LDL is endocytosed into cells with LDLR, receptor delivers LDL to lysosome, LDL breaks down, receptor recycles to surface

Question 25

LDLR mutations

Answer 25

Fall into 5 classes based on defect- I-V

Question 26

Class I LDLR mutation

Answer 26

No protein found

Question 27

Class II LDLR mutation

Answer 27

Cannot leave ER, degraded

Question 28

Class III LDLR mutation

Answer 28

Cannot bind LDL

Question 29

Class IV LDLR mutation

Answer 29

Do not migrate to coated pits (rare)

Question 30

Class V LDLR mutation

Answer 30

Cannot dissociate from LDL, not recycled to cell surface

Question 31

Possible therapies for FH

Answer 31

Decrease intake of cholesterol and fats, bile-acid binding resins (cholestyramine), statins block cholesterol synthesis

Question 32

Bile-acid binding resins

Answer 32

Limits recycling from intestine, liver increases synthesis of LDLR and cholesterol

Question 33

Statins for blocking cholesterol synthesis

Answer 33

HMG CoA reductase activity targeted, LDLR synthesis increased

Question 34

Hypertrophic cardiomyopathy

Answer 34

Half familial, autosomal dominant mutations in 10 genes for sarcomere- beta-myosin heavy chain (35%), myosin-binding protein C (20%), troponin T (15%)

Question 35

Dilated cardiomyopathy

Answer 35

1/3 familial, autosomal dominant, X-linked and mitochondrial mutations- actin, cardiac troponin T, desmin

Question 36

Long QT cardiomyopathy

Answer 36

Delayed repolarization due to affected potassium and sodium channels

Question 37

Factors in stroke

Answer 37

Mitochondrial disorder MELAS, mutations in NOTCH3 (also causes dementia), protein C and S mutations (normally inhibit clotting), factor V Leiden (increases clotting)

Question 38

Factors in hypertension

Answer 38

Present in a few single gene mutations as one symptom- Liddle syndrome, Gordon syndrome, rare disorders of corticosteroid production

Question 39

Liddle syndrome

Answer 39

Defective epithelial sodium channel (ENaC)

Question 40

Gordon syndrome

Answer 40

Increased renal salt reabsorption (WNK2 or WNK4 kinases)

Question 41

Type I diabetes

Answer 41

Early onset, immune destruction of pancreatic islet cells, lack of insulin

Question 42

Type II diabetes

Answer 42

Late onset, usually with obesity, peripheral insulin resistance

Question 43

MODY

Answer 43

Maturity onset diabetes of the young, intermediate onset, autosomal dominant pattern, no association with obesity

Question 44

Risks for type I diabetes

Answer 44

Siblings at increased risk, diabetic parent increases risk (higher for father), monozygotic twins are 30-50% concordant (not entirely genetic, autoimmune, specific viral infection)

Question 45

HLA association in type I diabetes

Answer 45

95% Caucasian type I, HLA DR3 or DR4, only 50% of generation population is DR3 or DR4, share with sibling, recurrence risk increased, no aspartate at position 57, 100x risk

Question 46

VNTR polymorphism

Answer 46

5' to insulin gene, may affect insulin transcription, insulin region polymorphism could account for 10% of familial clustering

Question 47

Risk for type II diabetes

Answer 47

90% of diabetes cases, high concordance in monozygotic twins, 10-15% recurrence in first degree relatives, obesity and positive family history are risks, increases with too much food and too little exercise

Question 48

Genes in type II diabetes

Answer 48

Mutations in calpain-10, common mutation in PPAR-gamma transcription factor gene- involved in adipocyte differentiation, increases risk by 25%, found in 75% of people of European descent

Question 49

MODY genes

Answer 49

1-5% of cases, autosomal dominant, glucokinase mutations in 50% of cases

Question 50

Transcription factors responsible for pancreatic development or insulin regulation

Answer 50

Hepatocyte nuclear factor 1 alpha (HNF1alpha) Hepatic nuclear factor 1 beta (HNF1beta) Hepatocyte nuclear factor 4 alpha (HNF4alpha) Insulin promoting factor 1 (IPF1) Neurogenic differentiation 1 (NEUROD1)

Question 51

Risks for obesity

Answer 51

BMI >30, leptin deficiency- leptin deficient humans are morbidly obese, neuropeptide Y and MCR4- appetite control, mutations in 3-5% of severely obese

Question 52

Alzheimer disease

Answer 52

10% over 65, 40% over 85, risk doubles if first-degree relative affected, few autosomal dominant cases, Presenilin-1 or -2, part of cleavage of APP precursor, gain of function mutants, some cases with APP mutation, certain ApoE alleles increase risk