Polygenic and Multifactorial Inheritance

Many disorders demonstrate familial clustering which does not conform to any recognized pattern of Mendelian inheritance.

Examples include: several of the most common congenital malformations many of the most common diseases of adult life
Congenital malformation Cleft lip/palate Adult onset diseases Diabetes mellitus

Congenital heart defects

Neural tube defects Pyloric stenosis Congenital dislocation of the hip

Hypertension
Ischemic heart disease Epilepsy Schizophrenia

Talipes

Glaucoma

A small fraction of these conditions are environmentally caused (e.g., congenital heart defects due to intrauterine rubella infection);
Another small fraction are caused by a single Mendelian gene (e.g., hyperbetalipoproteinemia associated with coronary artery disease).

However, most cases, especially

isolated cases without associated anomalies,

are determined in a more complicated manner, best explained by an additive polygenic model.

The term polygenic implies that the trait is determined by a large number of genes, each adding a small effect The term multifactorial implies that the trait has environmental as well as polygenic components. The term additive implies that the effects of the genes are cumulative, i.e. no one gene is dominant or recessive to another.

Continuous multifactorial traits

Most normal human characteristics are determined as continuous multifactorial traits

These traits by definition have a continuously graded distribution.

Height Weight Head circumference Skin colour

Intelligence Blood pressure Red cell size Dermatoglyphics (ridge count)

Continuous multifactorial traits

Nr.pers.

for height, there is a range from the very tall to the markedly short with the mean in Romanian of 170 cm. This takes the form of a symmetrical bell-shaped curve distributed evenly about a mean

140 150 160 170 180 190 200 210 cm.

The distribution of height in a population is Gaussian, with the majority of individuals centered around the mean. The spread of the distribution about the mean is determined by the standard deviation

Continuous multifactorial traits

Frecventa in populatie Frecventa in populatie aa Scund 2Aa Mediu AA nalt Genotip: aabb aaBb aaBB AaBB AABB Aabb AaBb AABb AAbb Fenotip: Scund I n t e r m e d i a r nalt Fenotip: Scund Frecvena n populaie Intermediar nalt

Genotip:
Fenotip:

Continuous multifactorial traits

Skin colour depends of quantity of melanin, a brown-black pigment, deposed as granules in skin cells. Skin pigmentation is different from a population to other. Natural selection to fix the most favorable combination of genes, depending on environmental conditions. E.g. the Scandinavian population, where for a short time are sunny days, has a little pigmentation, while the population from tropic has, contrary, o lot of pigments which protects the body from intensive sun radiation.

Skin pigmentation
The trait may be determined by 2-6 genes. In the most simple possibility, it is supposed the intervention of two pairs of allelic genes: Aa and Bb, with genes A and B determining a quantity of pigment equal with 1 and the genes a and b a quantity of pigment equal with 0. The blacks, dominant homozygous with genotype AA and BB have a quantity of pigment equal with 4 , and the whites, recessive homozygous with genotype aa and bb have a quantity of pigment equal with 0

Skin pigmentation
Black AA ; BB X White aa ; bb Aa ; Bb Aa ; Bb X

Gametes: AB = 2 AB = 2 AA/BB = 4 B AA/Bb = 3 DM Aa/BB = 3 DM Aa/Bb = 2 M Ab = 1 AA/Bb = 3 DM AA/bb = 2 M Aa/Bb = 2 M Aa/bb = 1 LM aB = 1 Aa/BB =3 DM Aa/Bb = 2 M aa/BB = 2 M aa/Bb = 1 LM ab = 0 Aa/Bb = 2 M Aa/bb = 1 LM aa/Bb = 1 LM aa/bb = 0 W

Ab = 1

aB = 1

ab = 0

Skin pigmentation

If the trait would be determined by 3 independent alleles,

the proportion would be:

B 1 DM 4 M 6 LM 4 W 1 1 6 15 20 15 6 1

In determining of skin colour interfere without the pigment quantity, other individual or environmental factors: sex, age, skin thickness, food, sunlight, etc. This is the reason that this type of trait is called, usually, polygenic, multifactorial

Discontinuous multifactorial traits

In the analysis of discontinuous trait it is first necessary to show that the incidence in members of affected families is increased above the general population incidence: If the incidence is not increased the condition is probably non-genetic;

If increased, the pedigree pattern is examined for evidence of single-gene inheritance;

If multifactorial inheritance is then suspected, studies of twin concordance and family correlation are necessary. These studies show that many congenital malformations and common diseases of adult life are inherited as multifactorial traits.

Discontinuous multifactorial traits

Cleft lip and palate is a congenital malformation inherited as a multifactorial trait Proportion of relatives affected versus general population

Relatives
Twins 1st degree 2nd degree 3rd degree Non relatives

Affected
MZ DZ Sibs Aunts & uncles Nephews & nieces First cousins General population

Proportion Affected
about 40% about 4% 3.2% - 4.9% 3.0% - 4.3% 0.6% - 0.8% 0.7% - 0.8% 0.3% 0.1%

Risk Factor

40 X 7X 3X 1X

The frequency of some discontinuous traits in relatives of an affected person

Frequency First-degree relatives 4% Seconddegree relatives 0,6% Thirddegree relatives 0,3% General population 0,1%

Trait Cleft lip

Spina bifida / anencephaly

Pyloric stenosis Epilepsy Schizophrenia

4%
2% 5% 10%

1,5%
1,0% 2,5% 4,0%

0,6%
0,4% 1,5% 2,0%

0,3%
0,3% 1,0% 1,0%

Manic depression

15%

5,0%

3,5%

1,0%

An Additive Polygenic Model with a Threshold

Non-affected No. of peaples

Threshold

Affected

Small number of genes

Great number of genes

The assumption of the polygenic model is that there is a sizeable number of different genes randomly distributed throughout the population (approximating the normal curve). In combination, they generate an increased risk in a few individuals whose gene complements include almost all of them, that is, enough to push them over the risk threshold. Development of a cleft lip depends on the number of high risk genes the individual has and on the intrauterine environment.

An Additive Polygenic Model with a Threshold

Number of people General Population
2nd degree relatives

Threshold

1st degree relatives

Liability

Since first degree relatives have, on average, 50% of their genes in common with the affected individuals, their average number of risk genes will be halfway between that of the average number of the general population and that of the average number of the affected individuals. The distribution of the second degree relatives will be shifted away from the mean of affected individuals, and their average number of risk genes will be 1/4 times greater than the mean of the general population. The distribution of the third degree relatives will approximate that of the general population

An Additive Polygenic Model with a Threshold

According to the 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

The liabilities of all individuals in a population form a continuous variable, which has a normal distribution in both the general population and in relatives of affected individuals. To account for a discontinuous phenotype (i.e. affected or not affected) with an underlying continuous distribution, it is proposed that a threshold exists above which the abnormal phenotype is expressed. In the general population the proportion beyond the threshold is the population incidence and among relatives the proportion beyond the threshold is the familial incidence.

Criteria for Multifactorial Determination

1. It is only necessary to assume polymorphism at a few loci , i.e., 2 common alleles at each of 4 or 5 gene loci give an approximately normal distribution of the genetic predisposition to develop the malformation.
2. Correlation between relatives is proportional to the genes they have in common, provided mating is random, there is no environmental variation, and the genes are additive. 3. The mean for the offspring is, on average, midway between a parental value (either one of the parental value) and the population mean, provided mating is random and there are insignificant environmental differences. 4. Risk to relatives declines sharply with increasingly distant degree of relationship. 5. Risk to relatives varies directly with the severity of the index case such that those with more severe degrees of the malformation are the more extreme deviants from the population mean.

Criteria for Multifactorial Determination

6. Risk to relatives depends upon the sex of the index case, with the risk being higher for relatives of a patient of the rarer sex. This is illustrated by the condition pyloric stenosis. Pyloric stenosis shows a male to female ratio of 5 to 1. The proportions of affected offspring of male index patients are 5,5% for sons and 2,4% for daughters, whereas the risks to the offspring of female index patients are 19,4% for sons and 7,3% for daughters. The probable explanation for these different risks is that in order for a female to be affected she has to lie at the extreme of the liability curve, so that her close relatives will also have a very high liability for developing the condition. As males are more susceptible to develop the disorder, risks in male offspring are higher than in female offspring regardless of the sex of the affected parent. 7. Risk to relatives depends upon the number of individuals already affected in the family, i.e., when parents have already had more than one affected child or one of the parents is affected, they are at a higher risk. 8. An increase in parental consanguinity is to be expected. The risk to subsequent sibs is higher when parents are consanguineous than when they are non-consanguineous (as opposed to autosomal recessive inheritance where the risk is the same).