Multifactorial Inheritance Flashcards
Multifactorial inheritance
Polygenic- many genes contribute to a trait, true for most quantitative traits, may show a normal distribution
Threshold model
Some diseases are only present or absent, distribution in population is not that of single genes
Liability distribution
Individuals at one end of the curve are affected
Threshold of liability
Limit separates normal from affected, may differ by sex or other factor
Recurrence risk
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
Specific indications
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
Locus heterogeneity
Mutations in different genes give similar phenotype, different families have different mutations, in any one family a single mutation in a single gene
Background effects on major genes
One gene accounts for significant variation, influenced by environment or modifier genes, overall effect is continuous distribution
Twin studies
Compare monozygotic (100%) to dizygotic twins (50%), determine relative recurrence rate of trait
Concordant
Both twins are affected
Discordant
One twin affected, one is not
Concordance rate
For qualitative traits
Intraclass correlation
For quantitative traits
Measuring heritability
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
Adoption studies
Compare inheritance of trait in adopted vs. natural children, compare adopted children from affected parents vs. adopted children of unaffected parents
Finding genes
More complex than single-gene traits, may be multiple causes- specific genes, phenocopies, look for quantitative trait loci (QTLs)
Phenocopies
Have trait but not with genetic cause, possibly environmental
Finding quantitative trait loci (QTLs)
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
Affected sib-pair method
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
Common multifactorial disorders
Identifying major genes aids in risk estimates, health problems to consider- heart disease, hypertension, diabetes
Heart disease
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
Family history
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
Familial hypercholesterolemia (FH)
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
LDL receptor
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
LDLR mutations
Fall into 5 classes based on defect- I-V
Class I LDLR mutation
No protein found
Class II LDLR mutation
Cannot leave ER, degraded
Class III LDLR mutation
Cannot bind LDL
Class IV LDLR mutation
Do not migrate to coated pits (rare)
Class V LDLR mutation
Cannot dissociate from LDL, not recycled to cell surface
Possible therapies for FH
Decrease intake of cholesterol and fats, bile-acid binding resins (cholestyramine), statins block cholesterol synthesis
Bile-acid binding resins
Limits recycling from intestine, liver increases synthesis of LDLR and cholesterol
Statins for blocking cholesterol synthesis
HMG CoA reductase activity targeted, LDLR synthesis increased
Hypertrophic cardiomyopathy
Half familial, autosomal dominant mutations in 10 genes for sarcomere- beta-myosin heavy chain (35%), myosin-binding protein C (20%), troponin T (15%)
Dilated cardiomyopathy
1/3 familial, autosomal dominant, X-linked and mitochondrial mutations- actin, cardiac troponin T, desmin
Long QT cardiomyopathy
Delayed repolarization due to affected potassium and sodium channels
Factors in stroke
Mitochondrial disorder MELAS, mutations in NOTCH3 (also causes dementia), protein C and S mutations (normally inhibit clotting), factor V Leiden (increases clotting)
Factors in hypertension
Present in a few single gene mutations as one symptom- Liddle syndrome, Gordon syndrome, rare disorders of corticosteroid production
Liddle syndrome
Defective epithelial sodium channel (ENaC)
Gordon syndrome
Increased renal salt reabsorption (WNK2 or WNK4 kinases)
Type I diabetes
Early onset, immune destruction of pancreatic islet cells, lack of insulin
Type II diabetes
Late onset, usually with obesity, peripheral insulin resistance
MODY
Maturity onset diabetes of the young, intermediate onset, autosomal dominant pattern, no association with obesity
Risks for type I diabetes
Siblings at increased risk, diabetic parent increases risk (higher for father), monozygotic twins are 30-50% concordant (not entirely genetic, autoimmune, specific viral infection)
HLA association in type I diabetes
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
VNTR polymorphism
5’ to insulin gene, may affect insulin transcription, insulin region polymorphism could account for 10% of familial clustering
Risk for type II diabetes
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
Genes in type II diabetes
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
MODY genes
1-5% of cases, autosomal dominant, glucokinase mutations in 50% of cases
Transcription factors responsible for pancreatic development or insulin regulation
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)
Risks for obesity
BMI >30, leptin deficiency- leptin deficient humans are morbidly obese, neuropeptide Y and MCR4- appetite control, mutations in 3-5% of severely obese
Alzheimer disease
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
