Multifactor_Inheritance_LeClaire_2023_Lawrence LeClaire.pptx

Multifactorial Inheritance Lawrence LeClaire, PhD November 29, 2023 Suggested Reading: Medical Genetics Chapter 12 Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordan...

Multifactorial Inheritance Lawrence LeClaire, PhD November 29, 2023 Suggested Reading: Medical Genetics Chapter 12 Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease Multifactorial Inheritance • Many genes contribute to trait – polygenic • True for most quantitative traits • Height and weight • Blood pressure • May show a Normal Distribution • Bell-shaped curve • Many genes with large or small additive effects • Environment often important to phenotype 7 ft 9 in 7 ft 1 in 6 ft 5 in 5 ft 4 in Multifactorial Inheritance • Many genes contribute to trait – polygenic • True for most quantitative traits • Height* and weight • Blood pressure • May show a Normal Distribution • Bell-shaped curve • Many genes with large or small additive effects • Environment often important to phenotype Distribution One gene, two alleles Distribution Two genes, two alleles Distribution Multiple genes and alleles The Threshold Model • Some diseases are only present or absent • However, distribution in population is not that of single genes • May be a Liability Distribution • Individuals at only one end of curve are affected Liability Distribution • Example – pyloric stenosis • Seen in 1/200 males and 1/1,000 females • Threshold of Liability separates unaffected from affected Recurrence Risk • Not simple like 25% for recessive disorder or 50% for dominant disorder (single-gene) • Situation is very complex • • • • Unknown number of genes Degree to which each gene and allele contributes Genetic constitution of parents not known Environmental influence also varies • Empirical risks are derived • Based on observation of other cases • Determine risks to relatives of probands, extend it to new cases Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease Specific Indications • Can be hard to distinguish from single-gene with complicating factors • Reduced penetrance, variable expression • Look for relative recurrence risks • • • • • Higher if more than one affected family member Higher if proband is more severely affected Higher if proband is of the less affected sex Decreases rapidly with more distant relationship Risk to siblings and offspring tends to often be √population risk – See Table 12.2 for examples Complex Single-Gene Traits • Locus heterogeneity • Mutations in different genes give similar phenotype • Different families have different mutations • In any one family, a single mutation in single gene • Background effects on major genes • One gene accounts for significant variation • Influenced by environment or modifier genes • Overall effect is continuous distribution • Many traits can fall into multiple categories Major Gene Distribution Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease Nature vs. Nurture • Role of environment important in many traits • Especially true of quantitative traits • Relative role needs to be determined • Will enhance recurrence risk estimates • Study types designed to determine role of environment and genetics • Twin studies • Adoption studies Twin Studies • Compare monozygotic to dizygotic twins • Identical vs. fraternal • 100% vs. ~50% genetic identity • Determine relative recurrence rate of trait • Categorize twin pairs • Concordant = both affected • Discordant = One affected, one not • Concordance rate - for qualitative traits • Intraclass correlation – for quantitative traits Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease Measuring Heritability • Compare MZ and DZ twin concordance rates • Estimated heritability is twice the difference heritability = 2(MZ-DZ) – See Table 12.3 for examples • Defined as proportion of variance of a trait that is determined by genes • Measured from 0 to 1 • Attributed to similarity of environment for twins • MZ often have more identical environments Adoption Studies • Compare inheritance of trait in adopted vs. natural children • Children born to affected parents and raised by them or adopted by unaffected parents • Compare adopted children from affected parents vs. adopted children of unaffected • Do children develop trait at same rate? • Many caveats Finding Genes • Not as simple as in single-gene traits • May be multiple causes • Some cases caused by specific genes • Some are phenocopies, with trait but not with genetic cause, possibly environmental • Molecular biology gives us new tools Finding Genes • Use a population with affected and unaffected members • Perform a genome scan • Check genetic constitution at many loci scattered throughout the genome – VNTRs, SNPs, etc. • Compare alleles at each locus with trait • Can locate regions which correlate with trait • Screen region for candidate genes Alternate Methods • No obvious subsets as starting point • Too demanding to screen thousands • Affected sib-pair method • • • • • • Two sibs affected with same disorder Share 50% of genes on average Must share genes causing effect Use pairs from many families Compare to each other, unaffected sibs Find regions in common in many pairs Genome Wide Association Study • GWAS now used for many studies • Similar in concept to affected sib pair study • Many individuals from many affected families • All possible family members tested using many markers, such as SNP microarray • Find areas with alleles in common in affected, different from unaffected Common Multifactorial Disorders • Genes influence most common health problems • Some major effects, many minor • Identifying major genes aids in risk estimates • Important 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 • One result can also be stroke • Many risk factors – obesity, cigarettes, hypertension, high cholesterol, positive family history Family History • Positive family history increases risk 2- to 7-fold • Greater risk when • More affected relatives • Affected relative is female (less affected sex) • Early age of onset for affected relative • All are consistent with rules for identifying multifactorial inheritance • Genetic factor – familial hypercholesterolemia Familial Hypercholesterolemia (FH) • Quantitative trait with a major gene • Autosomal dominant inheritance • Approximately doubles serum cholesterol • Accelerates atherosclerosis • Produces xanthomas (fatty deposits) • Much higher risk of coronary artery disease and myocardial infarction • Homozygotes more severely affected Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease LDL Receptor • Cholesterol is part of cell membranes • Synthesized or obtained from lipoprotein particles • LDL in blood bind to receptor on cells (LDLR) • Glycoprotein made in RER, pass through Golgi • LDL is endocytosed into cells with LDLR • Receptor delivers LDL to lysosome • Lysosome breaks down LDL • Receptor recycles to surface LDLR Cycle Classes of LDLR Mutations • Mutations fall into 5 classes based on defect • Class I – no protein found • Class II – Cannot leave ER, degraded • Class III – Cannot bind LDL • Class IV – Do not migrate to coated pits (rare) • Class V – Cannot dissociate from LDL, not recycled to cell surface Possible Therapies • Decrease intake of cholesterol and fats • Modest effect, cholesterol synthesized • Bile-acid binding resins (cholestyramine) • Limits recycling from intestine • Liver increases synthesis of LDLR and cholesterol • Statins block cholesterol synthesis • HMG CoA reductase activity targeted • LDLR synthesis increased • Combination therapy is best so far Objectives • Define the following terms in relation to multifactorial inheritance: • Multifactorial trait • Recurrence risk • Heritability Threshold of liability Concordant/discordant trait • Describe the five criteria for recurrence risk which indicate that a trait shows multifactorial inheritance • Describe the role of twin and adoption studies in differentiating between heredity and environmental influences in studying multifactorial traits • Be able to compute the heritability of a phenotype • Describe the role of the LDL receptor gene in familial hypercholesterolemia • Identify the genes involved in the following multifactorial disorders: • Diabetes (Type I, Type II, MODY) • Obesity • Alzheimer Disease Diabetes • Three basic classes of diabetes • Type I – Early onset, immune destruction of pancreatic islet cells, lack of insulin • Type II – late onset, usually with obesity, peripheral insulin resistance • MODY, Maturity Onset Diabetes of the Young intermediate onset, autosomal dominant pattern, no association with obesity Type I Diabetes • Siblings at increased risk, 6% vs. 0.4% • Diabetic parent increases risk, higher for father • MZ twins, 30 to 50% concordant, not entirely genetic – autoimmune, specific viral infection? • HLA association found – part of story • 95% Caucasian Type I, HLA DR3 or DR4 • Only 50% of general population is DR3 or DR4 • Share with sibling, recurrence risk goes to 20% • No aspartate at position 57 in DQ, 100X risk Other Genes and Type I • Variable Number Tandem Repeats (VNTR) polymorphism 5’ to insulin gene • May affect insulin transcription • Insulin region polymorphism could account for 10% of familial clustering Type II Diabetes • About 90% of cases of diabetes are Type II • Increasing in younger people in affluent areas • Very high concordance in MZ twins, >90% • Recurrence in first degree relatives 10-15% • Obesity and positive family history are risks • Risk increases with western diet and exercise patterns – too much food, too little exercise Genes and Type II • Linkage studies implicate some candidates • TCF7L2 is most significant (50% increase in risk) • Transcription factor involved in secreting insulin • KCNJ11- potassium channel necessary for glucosestimulated insulin secretion • 20% increase in susceptibility • Common mutation in PPAR-γ nuclear receptor • Involved in adipocyte differentiation • Increases risk by 25% • Found in 75% of people of European descent MODY Genes • 1-5% of diabetes cases, autosomal dominant • Glucokinase mutations in 50% of cases • Transcription factors responsible for pancreatic development or insulin regulation • • • • • Hepatocyte nuclear factor 1-α (HNF1α) Hepatic nuclear factor 1-ß (HNF1ß) Hepatocyte nuclear factor 4-α (HNF4α) Insulin promoter factor 1 (IPF1) Neurogenic differentiation 1 (NEUROD1) Obesity • Obesity defined as BMI > 30 • Many causes • Heritability estimates from 0.6 to 0.8 • Obese mutant mice – leptin deficiency • Leptin normal in most obese humans • Appetite control – neuropeptide Y and Melanocortin-4 Receptor (MC4R) • Mutations in 3-5% of severely obese Alzheimer Disease • Affects 10% of population older than 65; 40% older than 85 • 5 million Americans currently have AD • Amyloid plaques and neurofibrillary tangles are hallmarks of this disease • Risk of AD doubles if person has an affected first-degree relative • Presenilin 1, Presenilin 2, and APP mutations account for approximately half of early-onset cases • ApoE appears to be associated with clearance of amyloid from the brain; variations in ApoE can increase risk in certain populations Alzheimer Disease Other Disorders – Table 12-6 • Alcoholism • Schizophrenia • Bipolar • Autism spectrum • Hypertension • Parkinson Disease • ALS • Epilepsy Summary • Multifactorial inheritance – multiple genes • Environment is important in expression • Recurrence risk can help identify mode • Threshold of liability can explain present-absent phenotypes of multifactorial traits • Liability risk can vary by sex • Twin and adoption studies have proven useful • Common disorders often multifactorial • Some mutations contribute significantly to certain risks – FH • Different forms of diabetes have different risks, different genes play a role