Genetics of Common Disorders with Complex Inheritance

Question 1

Multifunction Disorders

Answer 1

Diseases that result from the interaction of multiple genes, often with additional influences of environmental factors. Most diseases are multifactorial.

Question 2

3 Characteristics of Multifactorial Disorders

Answer 2

1) Occurs more frequently in relatives of an affected individual than in the general population (relative risk ration is greater than 1)
2) Does not follow any of the classical mendelian inheritance patterns
3) The recurrence risk for a family member is determined using empirically derived risk tables for individual diseases when available

Question 3

Define the terms qualitative or dichotomous trait and quantitative or continuous trait and explain how they differ

Answer 3

Qualitative traits (or dichotomous traits) are the classical mendelian traits. They are either present or not present. Such an example would be if a pea is round or wrinkled. Quantitative traits (or continuous traits) are those that have a measurable phenotype that depend of the cumulative actions of many genes and the environment. Such examples are height, weight, IQ, blood pressure, etc.). Complex traits can be either qualitative or quantitative and this is why they are more complex. Simple mendelian rules simply can’t apply in these situations.

Comparions:

1) Mendelian traits are qualitative or dichotomous, they are either present or not.
2) Mendelian traits are almost always attributable to different alleles of single genes.
3) Mendelian traits follow simple rules of inheritance, permitting recurrence risk to be calculated for family members.
4) Complex traits can be either continuous (quantitative) like height, weight, etc or qualitative (present or absent)
5) Complex traits result from the contributions of multiple genes with or without environmental influences
6) Recurrence risk for a family member is determined using empirically generated risk tables that were generated from studies.
7) Large scale studies to identify genetic risk factors for diseases may make it possible to estimate the risk for an individual

Question 4

Explain how the multigenic theory of quantitative traits can be modified to account for the existence of qualitative or dichotomous traits that are inherited in a complex manner

Answer 4

For complex traits, the simple rules that describe mendelian inheritance cannot be used to calculate risk. Quantitative traits are described by a continuous distribution of numerical values that usually take the form of a Normal (Gaussian) Distribution about a population mean. For many traits, “normal” range=mean +/- 2 SD.

Traits governed by a large number of factors (genes) would display the same type of continuous distribution as seen for quantitative traits. As more genes or possibilities are added it will change the spread or variance. (SD=Square root of variance so Variance is SD^2). So as more genes are added, the curve becomes more spread out or “diluted”. With less genes there is a big peak.

Polygenic traits are characterized by a continuous distribution of values about a population mean. So how is it that polygenic disorders are qualitative (dichotomous) or mendelian like inheritance in nature where you either have it or you don’t. Douglas Falconer postulated an underlying continuously variable susceptibility that is polygenic and follows Gaussian distribution in the population. He further postulated a critical threshold value for the susceptibility above which these diseases are likely to manifest. This threshold is dependent on the disease.

Question 5

Define the term heritability in relation of complex traits

Answer 5

Complex traits are “heritable” but there are many genes that come into play and thus the risk can’t simply be determined like that of normal mendelian genetics. There are risk tables that will show what ones risk is for a disease based on inheriting it from a parent.

Question 6

Define the terms concordance and discordance

Answer 6

Concordance describes the likelihood that an individual will share a common phenotype with another family member, e.g. to be affected by the same disease. Discordance describes the likelihood of two family members will not share a common phenotype.

Those with a closer degree of relationship are likely to have a higher concordance.

Question 7

Define relative risk and describe how it is calculated.

Answer 7

The relative risk ratio is a quantitative measure of the degree of familial aggregation of a disease. (Lambda(r)).

LAMBDA(r) = Prevalence of the disease in the relatives of an affected person / Prevalence of the disease in the general population

If it is greater than 1, it shows that there is a genetic component to the disease.

Question 8

Describe monozygotic and dizygotic twinning

Answer 8

Monozygotic twins are identical twins that share an identical genome. Dizygotic twins are fraternal and thus do not contain identical genetic information. By studying twins, one can see if a disease is strictly genetic or if there are environmental factors that come into play as well. If the concordance in monozygotic twins is less than 100% (because they should hypothetically have the same disease) then it shows that it is more than just genetic and that other non genetic factors are likely playing a role. Greater concordance in monozygotic twins than dizygotic twins also shows that it is likely a genetic defect. If the monozygotic twins are separated (different environments) and still share a similar concordance to those that are not in different environments shows that genetic factors are more important than environmental ones.

Question 9

Estimate the proportion of alleles an individual has in common with another relative

Answer 9

This is determined via the degree of relatedness. Thus, close relatives are likely to share more genes in common that more distant relatives.

1) Monozygotic twins share 100%
2) Dizygotic twins are primary so share 50%
3) Parents and children are primary so share 50%
4) Second degree relatives like grandson and and grandparent are 25% (1/2)^2.

(1/2)^n where n is the degree of relationship

Question 10

Explain how concordance rates between monozygotic and dizygotic twins are used to evaluate the relative contributions of genes and environment to a complex disorder

Answer 10

Looking at monozygotic twins who have 100% same genetic material, one can see, if they are in different environments, if that played a role on disease expression. If they vary, it is likely because environmental factors came into play. Looking at dizygotic twins then, it should show a lower concordance in dizygotic twins than monozygotic twins because they should not contain 100% identical genome and thus not have the same disorder as frequently.

Question 11

Describe a normal or Gaussian distribution and explain its relevance to quantitative traits in a human population

Answer 11

Although complex disorders can be qualitative or quantitative, they can be explained in terms of disease susceptibility, which is a quantitative trait based on the interactions between multiple genes and environmental factors. Although there is no simple method to measure susceptibility for complex disorders, many important continuous (quantitative) biological traits like body mass index (BMI), blood pressure, forced expiratory values (FEV) and IQ can be measured. Some of these, like BMI can then be linked to diseases like heart disease. The distribution of values for quantitative traits in a population usually takes the form of a norm or Gaussian distribution.

A normal Gaussian distribution is described by two terms, mean and variance, which is equal to the square of the standard deviation. The value of the variance is related to the contribution of genes and environment to the trait.

Question 12

Mean

Answer 12

The mean is the “middle” or the highest point of the graph where all the others seems to be localize around. It is described by mu.

Question 13

Variance

Answer 13

Variance is equal to the square of the standard deviation.(SD^2). The value of the variance is related to the contribution of genes and environment to the trait. It is the measurement of the “spread” around the mean. The more spread out the graph is, the greater the variance, more compact, the smaller. Variances are additive when they are due to different causes e.g. genes and environment. Vp = Ve + Vg or SDp^2 = SDe^2 + SDg^2

Question 14

Standard Deviation

Answer 14

The SD = the square root of the variance. It is a defined percentage of the data and as the SD decreases, the variance will as well. The larger it is, the more spread out and shorter the curve, the smaller, the more compact and taller it is.

Question 15

Explain the relationship between variance and the contributions of genes and environment to quantitative traits

Answer 15

As more genes and environmental factors come into play, the variance tends to be even more spread, thus resulting in a normal curve that is more spread out and shorter. They determine the variance which determines the breadth of the curve

Question 16

Define heritability (h^2) and explain how twin studies are used to evaluate the heritability of a quantitative trait

Answer 16

Heritability (h^2) of a trait is the proportion of the total variance that is genetic.

It is a statistic used in breeding and genetics works that estimates how much of the genetic diversity of a phenotypic trait in a population is due to genetic differences in that population. Other causes of measured variation in a trait are characterized as environmental factors, including measurement error.

h^2 = Vg/Vp = SDg^2 / SDp^2

Twin Studies:

h^2 = Variance in DZ pairs - Variance in MZ pairs / Variance in DZ pairs

Values of h^2 should assume a value between 0 and 1. A value of 0 implies that the variability seen for a specific measurement is almost exclusively due to environment.

Values of h^2 that are about equal to 1 indicate that the variability observes is almost exclusively due to genes.

Question 17

Define the term modifier gene and explain how a modifier gene can account for such phenomenon as variable expressivity and incomplete penetrance

Answer 17

Instead of masking the effects of another gene, a gene can modify the expression of a second gene, this is a modifier gene. It can modify the expression.

Although most single gene disorders are inherited in a mendelian manner, their phenotype might vary even when due to the same mutant allele (variable expressivity). In some cases, there may be no evidence of an abnormal phenotype (incomplete penetrance). The different outcomes or phenotypes are thought to be due to the influence of environmental factors and/or other modifier genes.

Question 18

Describe the cause and pattern of inheritance of the digenic form of Retinitis Pigmentosa

Answer 18

This is the only digenic example we looked at. It is an incurable eye condition that progresses from night blindness to tunnel vision to legal blindness by middle age. It is the simplest example of a multigenic trait and it is determined by the additive effects of genotype sat multiple loci. There are no known environmental factors here.

Question 19

Identify the gene most commonly mutated in Hirschsprung disease and suggest an explanation for the existence of mendelian and complex forms of the disease

Answer 19

Hirschsprung (HSCR) is a loss of some ganglionic cells of the colon that control peristalsis and results in severe constipation. There is locus heterogeneity, in other words loss of a number of different genes can lead to the disease. This gives rise to forms that can be dominant, recessive, or multigenic. The mendelian forms also have variable expressivity and incomplete dominance which further complicates determining the risk factor. The gene most commonly mutated is the RET gene and specifically the 10q11.2.

Question 20

Describe the role of the Major Histocompatibility Complex (MHC) in Type I Diabetes

Answer 20

Type I (insulin-dependent) diabetes (IDDM) typically develops in childhood and is thought to be an autoimmune disease with a strong genetic component. It shows family aggregation with a relative risk ratio for siblings of an affected patient, (Lambda(s)), equal to about 35 and concordance rates of about 40% in monozygotic twins and 4% in siblings. The MHC is known to play a major role. The MHC is a very large genomic region that contains several families of related genes that participate in priming lymphocytes to mount an immune response. A cluster of genes at the MHC class II locus, designated HLA-DR, have been implicated in Type I IDDM. These genes are a haplotype that are usually inherited as a group, one from each parent. Because it is a haplotype, the more haplotypes you have in common with someone with the disease, the more likely you are to get the disease.

Question 21

Describe genetic and environmental factors that contribute to idiopathy cerebral vein thrombosis in young adult women

Answer 21

It is clots that form in the brain.

There are 3 common factors, 2 genetic, 1 environmental:

1) Mutant allele of factor V: Arg506Gly, factor V Leiden. With this mutation there is more Factor V around and doesn’t get degraded. It then feeds into a higher frequency of forming a clot. Frequency is about 5% and this mutation increases your risk by 7 to 8 fold.
2) Mutant allele for Prothrombin: 20210G>A. Occurs in 3’ untranslated region. Has an influence on the mRNA stability. It increases prothrombin stability getting higher levels of it. Carrier frequency is 2.5% and increases risk 4-6 fold
3) Oral contraceptives: Increase plasma levels of Factor X and Prothrombin. When combined with another mutation it increases risk even more. 20 fold greater with one mutation, 150 fold with both.

Question 22

Describe the relationship between apolipoprotein E alleles and Alzheimers disease.

Answer 22

APOE is associated with late onset of Alzheimers. The genes are not yet known that cause this, but they are increasing with age and differ between sex (females are more affected than males). APOE is a constituent of these protein aggregates that form in the brain. E4 predisposes an individual. There is an associate between which alleles you get and your predisposition.

There are mendelian versions that are dominant but the late onset Alzheimers is associated with complex causes.

Question 23

List the 4 most common types or categories of congenital malformations

Answer 23

1) Neural Tube Defects
2) Cleft lip with or without cleft Palate
3) Congenital Heart defects
4) Pyloric Stenosis
5) Hip Dysplasia

Question 24

Identify the major environmental factor associated with neural tube defects

Answer 24

Folic acid deficiency

Question 25

List two highly prevalent mental disorders that are known to have a genetic component

Answer 25

1) Schizophrenia
2) Bipolar Disorder

Likely to be multigenic

Question 26

Understand the purpose and use of empirical tables in determining the recurrence risk for complex disorders

Answer 26

Because multiple factors that are both genetic and environmental come into play, these can not be calculated via typical inheritance patterns. Tables have been generated from studies to use.

Question 27

Predict the approximate recurrence risk for relatives of a proband diagnosed with a multigenic disorder from the known population risk for the disorder

Answer 27

You have to look at the individuals and how they are related to the proband to determine the risk because it differ for every disorder.