Polygenic Disorders are those which result from an interaction between multiple genes and often multiple environmental factors
By Live Dr - Sun Jan 11, 1:04 pm
Major Types of Genetic Diseases:
Somatic Cell Genetic Diseases
Although many human diseases are inherited as simple Mendelian traits or are associated with chromosomal abnomalities, most of the common diseases of adult life (e.g., diabetes mellitus, hypertension, schizophrenia)and most common congenital malformations(e.g., cleft lip, cleft palate, neural tube defect)are not. Yet, there is considerable evidence that genetic factors are important in their etiology. At the same time, multiple environmental factors contribute to these diseases.
Polygenic Disorders are those which result from an interaction between multiple genes and often multiple environmental factors.
1. Most of common diseases and common congenital malformation
2. Caused by the genetic basis and tend to aggregate in families.
3. Recurrence rate ≈ 1%～10%
4. Resulting from the impact of multiple genes and multiple environmental factors
This genetic predisposition to disease is thought to reflect the cumulative effect of genetic variation at several and possibly multiple loci, each with a relatively small effect on phenotype. We define as polygenic those traits or diseases caused by the impact of many different genes, each having only a limited individual impact on phenotype, and as multifactorial those traits resulting from the interplay of multiple environmental factors with multiple genes. In practice, the terms are oftend used interchangeably.
Polygenic traits are usually quantitative rather than qualitative in nature and are frequently distributed continuously in the population, often in a more or less normal (Gaussian) frequency distribution, e.g., height and blood pressure.
Qualitative Trait and Quantitative Trait
Qualitative trait: Monogenic trait, genetic traits which are present or absent. One has the trait or not.
The variation of this trait in a group is not continuous.(e.g. Height of pituitary dwarfism & normal)
Quantitative trait: polygenic trait, genetic traits which are measurable characteristics.
The distribution of this trait in a group is continuous, and there is only one peak.(e.g. height)
To understand the normal distribution of quantitative trait, consider the hypothetical example of two independent genetic loci, A and B, which affect height. Each has two alleles, A(tall) and a(short), and B(tall) and b(short). Then this would lead to a phenotypic distribution of five groups in a ratio of 1 (4 tall genes) to 4 (3 tall + 1) to 6 (2 tall + 2 short) to 4 (1 tall + 3 short) to 1 (4 short). For a system with three loci each with two alleles the phenotypic ratio would be 1-6-15-20-15-6-1. It can be seen that as the number of loci increases, the distribution increasingly comes to resemble a smooth normal curve. The effects of environmental factors may further modify the shape of the frequency distribution.
The multifactorial model is then:
1. Several, but not an unlimited number, loci are involved in the expression of the trait.
2. There is no dominance or recessivity at each of these loci.
3. The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype.
4. The environment interacts with the genotype to produce the final phenotype.
Threshold model of disease
If multifactorial traits are quantitative traits with continuous distribution, how can they control diseases, such as cleft lip or spina bifida? One either has the disease or doesn’t. There is no intermediate. Multifactorial diseases are best explained by the threshold model.
According to the liability/threshold model, all of the factors which influence the development of a multifactorial disorder, whether genetic or environmental, can be considered as a single entity known as liability.
Liability: be a measure of all of the factors that affect the probability of multifactorial disorder, both genetic (innate) and environmental.
The liabilities of all individuals in a population form a continuous variable, which has a normal distribution in the general population .
As the number of multifactorial genes for the trait increases, the liability for the disease increases. When it reaches a threshold, the liability is so great that abnormality, what we call disease, results. In the general population the proportion beyond the threshold is the population incidence.
In relatives of affected individuals, the liabilities also form a continuous variable, which has a normal distribution. However, the curves for these relatives will be shifted to the right, with the extent to which they are shifted being directly related to the closeness of their relationship to the affected index case.
It is important to emphasize once again that liability includes all factors that contribute to the cause of the condition. Looked at very simply, a deleterious liability can be viewed as consisting of a combination of several ‘bad’ genes and adverse environmental factors. Liability cannot be measured but the mean liability of a group can be determined from the incidence of the disease in that group using statistics of the normal distribution. The units of measurement are standard deviations and these can be used to estimate the correlation between relatives.
As the discussion above, there is considerable evidence that genetic factors are important in their etiology. So, we have a new word–heritability(H).
Heritability: Measure (%) of the proportion of the total phenotypic variance that is due to the genetic basis.
If H is high — phenotypic variation is largely genetic
If H is low — phenotypic variation is largely environmental
Estimates of the heritability of a condition or trait provide an indication of the relative importance of genetic factors in its causation, so that the greater the value for the heritability the greater the role of genetic factors. Heritability is estimated from the degree of resemblance between relatives expressed in the form of a correlation coefficient which is calculated using statistics of the normal distribution. Alternatively, heritability can be calculated using data on the concordance rates in monozygotic and dizygotic twins. In practice it is desirable to try to derive heritability estimates using different types of relatives, and to measure the disease incidence in relatives reared together and living apart so as to try to disentangle the possible effects of common environmental factors.
Estimates of heritability for some common diseases are given in Table.
Inheritance Characteristics of Polygenic Disease
1. Aggregate but do not segregate in families.
2. First degree relatives have the same risk of affected.
3. Risk of affected relatives falls off very quickly with the degree of relationship.
4. Consanguinity also increases the probability of an affected child for a multifactorial trait.
5. Variation among populations.
Estimate of Recurrence Risk
1. Incidence and Heritability
If the disease has these characteristics( Incidence≈0.1%~1%,Heritability≈70%~80%), Recurrence Risk of first-degree relatives of patients can be calculated by Edward formula.
f =√P(f－recurrence risk, P－incidence in population). For example, the incidence of cleft lip is 0.17%, and heritability is 76%, so its f=√0.17%=4.1%.
2.The risk increases with the number of affected relatives. For an autosomal recessive disease such as cystic fibrosis, the recurrence risk for a sibling of an affected child is 25%,whether that family has previously had one, two, or several affected children. In contrast, the recurrence risk for a sibling of child with cleft palate, is approximately 4%; whereas that risk increases to more than10% if there are two affected first-degree relatives such as two siblings or a parent and a sibling. The presence of a second affected individual does not alter the risk per se; however, it suggests the family is further to the right in the distribution of genetic liability. Therefore, this family can be identified as having a higher than average recurrence risk.
3.The risk increases with the severity of the malformation or disease. The recurrence risk for a sibling of a child with unilateral cleft lip without cleft palate is approximately 2.5%, whereas the recurrence risk for a sibling of a child with bilateral cleft 1ip and cleft palate is approximately 6%. This reflect the assumption that the more severe the defect, the greater the underlying genetic liability, and, therefore, the placement of the severely affected individual further to the right on the distribution curve.
4.When the sex ratio of affected probands deviates significantly from unity, offspring of affected probands of the less frequently affected sex are at higher relative risk. If the two sexes have a different probability of being affected, thresholds of two sexes are different. Congenital pyloric stenosis, an obstruction to the stomach outlet caused by muscular hypertrophy, is five times more common in boys than in girls. This suggests that the threshold for genetic liability for girls is higher than for boys. Therefore, an affected girl might be expected to have a higher degree of genetic liability, and her relatives should have higher recurrence risks than those of an affected boy. In fact, children of affected females are three times more likely to have this same malformation than children of affected males. However, male offspring are still at higher absolute risk than are female.
1.Qualitative Trait; Quantitative Trait; Susceptibility; Liability; Threshold; Heritability
2.How to estimate the recurrence risk of first-degree relatives of polygenic disease patients