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:

Monogenic Disease

Polygenic Disease

Chromosome Disease

Somatic Cell Genetic Diseases

Polygenic Disorders

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

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